Re: 과당 pathogen 탐구... 22년 영향력지수 33점 논문...

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Cell Metab. Author manuscript; available in PMC 2022 Feb 7.

Published in final edited form as:

Cell Metab. 2021 Dec 7; 33(12): 2316–2328.

Published online 2021 Oct 6. doi: 10.1016/j.cmet.2021.09.004

PMCID: PMC8665123

NIHMSID: NIHMS1748090

PMID: 34619076

“Sweet death”: Fructose as a metabolic toxin that targets the gut-liver axis

Mark A. Febbraio1,* and Michael Karin2,*

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The publisher's final edited version of this article is available free at Cell Metab

SUMMARY

Glucose and fructose are closely related simple sugars, but fructose has been associated more closely with metabolic disease. Until the 1960s, the major dietary source of fructose was fruit, but subsequently, high-fructose corn syrup (HFCS) became a dominant component of the Western diet. The exponential increase in HFCS consumption correlates with the increased incidence of obesity and type 2 diabetes mellitus, but the mechanistic link between these metabolic diseases and fructose remains tenuous. Although dietary fructose was thought to be metabolized exclusively in the liver, evidence has emerged that it is also metabolized in the small intestine and leads to intestinal epithelial barrier deterioration. Along with the clinical manifestations of hereditary fructose intolerance, these findings suggest that, along with the direct effect of fructose on liver metabolism, the gut-liver axis plays a key role in fructose metabolism and pathology. Here, we summarize recent studies on fructose biology and pathology and discuss new opportunities for prevention and treatment of diseases associated with high-fructose consumption.

포도당과 과당은 밀접한 관련이 있는 단당류이지만 과당은 대사 질환과 더 밀접한 관련이 있습니다.  1960년대까지 과당의 주요 식이 공급원은 과일이었지만, 이후 고과당 콘시럽(HFCS)이 서구 식단의 주요 성분이 되었습니다. HFCS 소비의 기하급수적인 증가는 비만 및 제2형 당뇨병의 발병률 증가와 관련이 있지만, 이러한 대사 질환과 과당 사이의 메커니즘적 연관성은 아직 미약합니다.

식이 과당은 간에서만 대사되는 것으로 생각되었지만, 

소장에서도 대사되어 

장 상피 장벽을 악화시킨다는 증거가 나왔습니다. 

이러한 연구 결과는 유

전성 과당 불내증의 임상 증상과 함께 

과당이 간 대사에 미치는 직접적인 영향과 함께 

장-간 축이 과당 대사 및 병리에서 중요한 역할을 한다는 것을 시사합니다. 

여기에서는 과당 생물학 및 병리에 대한 최근 연구를 요약하고 고과당 섭취와 관련된 질병의 예방 및 치료를 위한 새로운 기회에 대해 논의합니다.

INTRODUCTION

Glucose is the major circulating carbohydrate in animals, whereas sucrose, a disaccharide consisting of glucose and fructose, is the major circulating carbohydrate in plants. However, certain fruits, such as figs, dates, mangoes, and pears, contain high amounts of free fructose. As humans have always consumed plants and fruits, fructose is a basic component of our diet and, for a long time, was considered neutral or even beneficial (Rippe and Angelopoulos, 2015). Nevertheless, the overconsumption of refined sugars, high-fructose corn syrup (HFCS) in particular, is increasingly considered as a major contributor to the growing incidence of a myriad of so-called lifestyle diseases. These include type 2 diabetes mellitus (T2DM); non-alcoholic fatty liver disease (NAFLD) and its aggressive form, non-alcoholic steatohepatitis (NASH); certain cancers, especially those of the liver, pancreas, and colon; and cardiovascular and kidney diseases. Although HFCS has been banned in several countries, it still accounts for approximately 40% of caloric sweeteners in the USA (White, 2008). Instead of being an equimolar mix of fructose and glucose as in sucrose, semi-artificial HFCS contains 25%–50% more fructose than glucose (Tappy and Lê, 2010). Much of the large increase in the sugar content of the Western diet is due to sweetened beverages—not only sodas but also fruit juices and sport drinks. On average, such drinks contribute to ~5% of daily caloric intake and 2 in 3 high-school-aged children in the USA consume at least one of these beverages per day (Kit et al., 2013).

포도당은 동물의 주요 순환 탄수화물인 반면, 

포도당과 과당으로 구성된 이당류인 자당은 

식물의 주요 순환 탄수화물입니다.  

그러나 

무화과, 대추야자, 망고, 배와 같은 특정 과일에는 

유리 과당이 다량 함유되어 있습니다. 

인간은 

항상 식물과 과일을 섭취해 왔기 때문에 

과당은 우리 식단의 기본 구성 요소이며 

오랫동안 중립적이거나 심지어 유익한 것으로 간주되었습니다(Rippe and Angelopoulos, 2015). 

그럼에도 불구하고 정제 설탕, 

특히 고과당 옥수수 시럽(HFCS)의 과잉 섭취는 

소위 생활습관병의 발병률을 높이는 주요 원인으로 점점 더 많이 거론되고 있습니다.

여기에는 

제2형 당뇨병(T2DM), 

비알코올성 지방간 질환(NAFLD) 및 

그 공격적인 형태인 비알코올성 지방간염(NASH), 

특정 암, 특히 간, 췌장, 결장암, 

심혈관 및 신장 질환 등이 포함됩니다. 

HFCS는 여러 국가에서 사용이 금지되었지만 

미국에서는 여전히 칼로리 감미료의 약 40%를 차지하고 있습니다(White, 2008). 

자당처럼 

과당과 포도당이 등가로 혼합된 것이 아니라 

반인공 과당인 HFCS는 포도당보다 과당이 25%~50% 더 많이 함유되어 있습니다(Tappy and Lê, 2010). 

서구식 식단의 당 함량이 크게 증가한 것은 

탄산음료뿐만 아니라 

과일 주스, 스포츠 음료 등 

가당 음료 때문이기도 합니다. 

평균적으로 이러한 음료는 일일 칼로리 섭취량의 약 5%를 차지하며, 미국 고등학생 3명 중 2명은 하루에 적어도 한 잔 이상 이러한 음료를 섭취합니다(Kit et al., 2013).

FRUCTOSE CONSUMPTION AND HEALTH: CLUES FROM HISTORY

It is widely believed that cane sugar (sucrose) was first used by humans in Polynesia, from where it spread to India. In the early centuries AD, Indians perfected the refining of cane sugar to crystal granules (Deerr, 1949). Cane sugar manufacturing had spread to the medieval Islamic world, where it was very expensive and was referred to as a “fine spice” and used for medicinal purposes. After the discovery of America, sugar cane culturing was introduced to the Caribbean, which supplied sugar to Europe (Deerr, 1949) and the United Kingdom, where sugar consumption increased by 1,500% in the 18th and 19th centuries. Despite this substantial growth, sugar consumption was not linked to increased metabolic disease risk until the 20th century. In the late 19th century, obesity, referred to as corpulence, affected less than 4% of the population (Osler, 1893) and T2DM affected 2 people per 100,000 (Johnson et al., 2017). As reviewed by Johnson and coworkers (Johnson et al., 2017), it was not until the early 20th century that a British physician stationed in India by the name of Sir Richard Havelock Charles made the observation that T2DM was increasing at a rapid rate among sugar-consuming, wealthy Indians living in Calcutta, but it was almost non-existent in poorer areas of India, where sugar consumption was nil. Sir Fredrick Banting, the Nobel laureate for medicine and physiology for his discovery of insulin, also hypothesized that refined sugar consumption could be linked to T2DM (Banting, 1926), but this was challenged by other notable scientists of the time, including Elliot Joslin, who believed that overeating and lack of physical activity led to metabolic diseases (Joslin and Lahey, 1934). Whether sugar consumption is a cause of modern-day obesity and T2DM still remains controversial (Khan and Sievenpiper, 2016).

사탕수수 설탕(자당)은 

폴리네시아에서 인류가 처음 사용했으며, 

이곳에서 인도에 전파된 것으로 널리 알려져 있습니다.  

서기 초기에 인도인들은 

사탕수수 설탕을 수정 과립으로 정제하는 기술을 완성했습니다(Deerr, 1949). 

사탕수수 설탕 제조는 

중세 이슬람 세계로 퍼져나갔으며, 

당시에는 매우 비싸서 '고급 향신료'로 불리며 의약용으로 사용되었습니다. 

미국 발견 이후 사탕수수 재배는 

카리브해에 도입되어 유럽(Deerr, 1949)과 영국에 설탕을 공급했으며, 

18~19세기에는 설탕 소비량이 1,500% 증가했습니다. 

이러한 상당한 증가에도 불구하고 설탕 소비는 20세기까지 대사성 질환 위험 증가와 관련이 없었습니다.19세기 후반에는 비만으로 불리는 비만 인구가 전체 인구의 4% 미만이었고(Osler, 1893), T2DM은 10만 명당 2명이었습니다(Johnson et al., 2017). 

Johnson과 동료들이 검토한 바에 따르면(Johnson et al., 2017), 

20세기 초에야 인도에 주재하던 영국인 의사 리처드 해브록 찰스 경이 

캘커타에 거주하는 설탕 소비가 많고 

부유한 인도인 사이에서 T2DM이 빠른 속도로 증가하고 있지만 

설탕 소비가 거의 없는 인도 빈곤 지역에서는 거의 존재하지 않는다는 관찰을 하게 되었습니다. 

인슐린 발견으로 노벨 의학 및 생리학상을 수상한 

프레드릭 밴팅 경도 정제 설탕 섭취가 T2DM과 관련이 있을 수 있다는 가설을 세웠지만(밴팅, 1926), 

과식과 신체 활동 부족이 대사 질환을 유발한다고 믿었던 

엘리엇 조슬린 등 당시의 다른 저명한 과학자들의 반박을 받았습니다(조슬린과 라헤이, 1934). 

설탕 섭취가 현대 비만과 T2DM의 원인인지 여부는 여전히 논란의 여지가 있습니다(Khan과 시븐파이퍼, 2016).

It is important to note that, according to the United States Department of Agriculture (USDA), the estimated per capita consumption of refined sugar has actually decreased in the past 50 years, but HFCS consumption has increased, such that by the mid-1990s it exceeded refined sugar consumption (Tappy and Lê, 2010). As the cost of sugar refinement grew in the mid-20th century, the industry was looking for cheaper alternatives, and in the late 1950s, scientists in the USA and Japan developed HFCS as a cheaper and sweeter sucrose substitute (Hanover and White, 1993). HFCS was also found to have a longer shelf life compared with cane sugar, leading to its increasing popularity as a sweetener and food additive in the latter part of the 20th century (White, 2008).

미국 농무부(USDA)에 따르면 

지난 50년 동안 정제 설탕의 1인당 소비량은 실제로 감소했지만 

HFCS 소비량은 증가하여 1990년대 중반에는 정제 설탕 소비량을 넘어섰다는 점에 주목할 필요가 있습니(Tappy and Lê, 2010). 

20세기 중반 설탕 정제 비용이 증가함에 따라 

업계에서는 더 저렴한 대안을 찾고 있었고, 

1950년대 후반 미국과 일본의 과학자들은 

더 저렴하고 단맛이 나는 자당 대체물로 HFCS를 개발했습니다(Hanover and White, 1993). 

또한 HFCS는 

사탕수수 설탕에 비해 유통기한이 더 긴 것으로 밝혀져

 20세기 후반에 감미료 및 식품 첨가물로 인기가 높아졌습니다(White, 2008).

GLUCOSE VERSUS FRUCTOSE: GASTROINTESTINAL (GI) METABOLISM

For many years, fructose and glucose were claimed to be indistinguishable in their health effects, but most recent studies suggest that fructose is the more deleterious of the two monosaccharides. The early dogma that fructose and glucose are equivalent is understandable, given that they are both hexoses with the same chemical formula C6H12O6. However, critically, fructose possesses a keto group in position 2 of its carbon chain, whereas glucose possesses an aldehyde group at position 1. Unlike glucose, which is mobilized by phosphofructokinase and glucokinase, the latter being an enzyme whose activity is subject to feedback inhibition and regulation by insulin, fructose is mobilized by the faster and constitutively active enzyme fructokinase (also known as ketohexokinase or KHK) (Geidl-Flueck and Gerber, 2017) (Figure 1).

수년 동안 과당과 포도당은 

건강에 미치는 영향이 다르지 않다고 주장되어 왔지만, 

최근 연구에 따르면 과당이 두 단당류 중 더 해롭다고 합니다.  

과당과 포도당이 동일한 화학식 C6H12O6의 육당류라는 점에서

 과당과 포도당이 동일하다는 

초기 도그마는 이해할 수 있습니다. 

그러나 

결정적으로 과당은 

탄소 사슬의 2번째 위치에 케토기가 있는 반면, 

포도당은 1번째 위치에 알데히드기가 있습니다. 

포스포프락토키나제와 

글루코키나제(후자는 인슐린에 의해 

활동이 피드백 억제 및 조절되는 효소)에 의해 동원되는 포도당과 달리

과당은

더 빠르고 구성적으로 활성화되는 효소인

프락토키나제(케토헥소키나제 또는 KHK라고도 함)에 의해

동원됩니다(Geidl-Flueck and Gerber, 2017)(그림 1).

As KHK is not feedback inhibited, its action results in rapid and robust conversion of fructose to fructose-1 phosphate (F1P), a potentially toxic intermediate that will be discussed further on. Although dietary fructose was initially thought to be metabolized exclusively in the liver, to which it is delivered by the portal circulation (Lyssiotis and Cantley, 2013; Vos and Lavine, 2013), it is now clear that dietary fructose is also metabolized at its site of absorption, the small intestine (Jang et al., 2018; Mayes, 1993), particularly when it is consumed at physiological concentrations. Whether fructose presents as pure fructose, sucrose, or HFCS, it is transported intracellularly via GLUT5 (also known as SLC2A5), a transporter expressed at the apical pole of the enterocyte luminal membrane with a high affinity (Km = 6.0 mM) for fructose (Douard and Ferraris, 2008; Patel et al., 2015) (Figure 2). In mice, the deletion of GLUT5 markedly reduces fructose absorption and leads to colonic dilation and flatulence (Barone et al., 2009), results that are likely to be of direct human relevance.

KHK는 

피드백이 억제되지 않기 때문에 

이 효소의 작용으로 과당이 독성이 있을 수 있는 중간체인 

과당-1 인산염(F1P)으로 빠르고 강력하게 전환됩니다(추후에 설명할). 

처음에는 

식이 과당이 

문맥 순환을 통해 전달되는 간에서만 대사되는 것으로 생각되었지만(Lyssiotis and Cantley, 2013; Vos and Lavine, 2013), 

이제는 식이 과당이 흡수 부위인 소장에서도 대사되며, 

특히 생리적 농도로 섭취할 경우 

더욱 그러하다는 것이 밝혀졌습니다(Jang et al., 2018; Mayes, 1993).

과당은 

순수 과당, 자당 또는 HFCS 형태로 존재하든 

과당에 대한 높은 친화력(Km = 6.0 mM)을 가진

 장세포 내막의 정극에서 발현되는 수송체 GLUT5(SLC2A5라고도 함)를 통해 

세포 내로 운반됩니다(Douard and Ferraris, 2008; Patel et al., 2015)(그림 2). 

생쥐에서 GLUT5를 제거하면 

과당 흡수가 현저히 감소하고 

대장 확장 및 헛배 부름이 발생하며(Barone et al., 2009), 

이는 인간과 직접적인 관련이 있을 가능성이 있는 결과입니다.

Fructose absorption can be limited in some humans that have a low absorption capacity and develop flatulence and diarrhea if they consume moderate to high amounts of fructose (Ravich et al., 1983), particularly if the fructose is free and not ingested as sucrose (Truswell et al., 1988). The molecular mechanisms that account for aberrant fructose metabolism are not fully understood, but they may be related to aging (Ferraris et al., 1993) and co-ingestion of other macronutrients, such as lipids (Perin et al., 1997). In addition, both the intestinal thioredoxin-interacting protein (TXNIP) (Dotimas et al., 2016) and the carbohydrate-responsive element-binding protein (ChREBP) (Iizuka et al., 2004; Kim et al., 2017b) are implicated in the regulation of GLUT5 and subsequent systemic fructose tolerance. Whether any of these proteins can be targeted to enhance fructose absorption, to the best of our knowledge, has not been investigated. These key findings, along with the clinical manifestations of hereditary fructose intolerance (HFI) discussed further on, suggest that the GI tract plays a key role in fructose metabolism and pathology.

과당 흡수 능력이 낮은 일부 사람의 경우 

과당 흡수가 제한될 수 있으며, 

특히 과당을 자당으로 섭취하지 않고 

유리 과당으로 섭취하는 경우(Ravich et al., 1983) 

중등도에서 다량의 과당을 섭취하면 

헛배 부름과 설사를 유발할 수 있습니다(Truswell et al., 1988). 

비정상적인 과당 대사를 설명하는 분자 메커니즘은 

완전히 이해되지 않았지만 

노화(Ferraris 등, 1993) 및 지질과 같은 다른 다량 영양소의 

동시 섭취와 관련이 있을 수 있습니다(Perin 등, 1997). 

또한 

장 티오레독신 상호 작용 단백질(TXNIP)(Dotimas 외, 2016)과 

탄수화물 반응성 요소 결합 단백질(ChREBP)(Iizuka 외, 2004; Kim 외, 2017b)은 

GLUT5와 그에 따른 전신 과당 내성 조절에 관여하고 있습니다. 

이러한 단백질 중 

과당 흡수를 향상시키기 위해 표적으로 삼을 수 있는 

단백질이 있는지 여부는 

우리가 아는 한 조사되지 않았습니다. 

이러한 주요 연구 결과는 

유전성 과당 과민증(HFI)의 임상 증상과 함께 

위장관이 과당 대사 및 병리에서 중요한 역할을 한다는 것을 시사합니다.

Figure 1.

Fructose metabolism

After ingestion, fructose is metabolized either in the gastrointestinal tract or the liver. Fructose is initially mobilized by the constitutively active enzyme ketohexokinase (KHK), which converts it to fructose 1 phosphate (F1P) that is subsequently cleaved by the rate limiting enzyme aldolase B to glyceraldehyde (GA) and dihydroxyacetone phosphate (DHAP). GA undergoes a series of subsequent metabolic conversions to form pyruvate, from which it can be converted to lactate, undergoes oxidative metabolism via the tricarboxylic acid (TCA) cycle, or feed de novo lipogenesis after the generation of acetyl and malonyl coenzyme A (CoA), finally generating triacylglyceride (TAG). The formation of malonyl CoA can alter the balance between fatty acid oxidation (FAO) and synthesis through an effect on acetyl-CoA carboxylase (ACC), resulting in the inhibition of AMP-activated protein kinase (AMPK), which stimulates FAO and carnitine palmitoyltransferase I (CPT1), which control the entry of fatty acids into the mitochondrion. ATP citrate lyase (ACLY), which uses cytosolic citrate to generate acetyl-CoA, is also upregulated by fructose consumption. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) converts DHAP to glycerol-3 phosphate (G3P), which, together with fatty acids, generates TAG.

과당은 

섭취 후 위장관이나 간에서 대사됩니다.  

과당은 

처음에 구성 활성 효소인 케토헥소키나제(KHK)에 의해 동원되어 

과당 1 인산염(F1P)으로 전환되고, 

이후 속도 제한 효소인 알돌라제 B에 의해 

글리세랄데히드(GA)와 디하이드록시아세톤 인산염(DHAP)으로 분해됩니다. 

GA는 

일련의 후속 대사 전환을 거쳐 

피루베이트를 형성하고, 

이로부터 젖산염으로 전환되거나 트리카르복실산(TCA) 사이클을 통해 산

화 대사를 거치거나 아세틸 및 말로닐 코엔자임 A(CoA) 생성 후 

새로운 지방 생성을 촉진하여 

최종적으로 트리아실글리세리드(TAG)를 생성할 수 있습니다. 

말로닐 CoA의 형성은 

아세틸-CoA 카르복실라제(ACC)에 영향을 미쳐 

지방산 산화(FAO)와 합성 사이의 균형을 변화시켜 

미토콘드리아로의 지방산 유입을 조절하는 

AMP 활성화 단백질 키나제(AMPK)와 

카르니틴 팔미토일 트랜스퍼라제 I(CPT1)의 억제를 초래하여 

지방산 산화를 촉진하는 결과를 초래할 수 있습니다. 

세포질 구연산염을 사용하여 

아세틸-CoA를 생성하는 ATP 구연산염 분해효소(ACLY)도 

과당 섭취에 의해 상향 조절됩니다. 

글리세랄데히드 3인산 탈수소효소(GAPDH)는 

DHAP를 글리세롤-3 인산염(G3P)으로 전환하여 

지방산과 함께 TAG를 생성합니다.

Figure 2.

Fructose absorption at different sites

Fructose and glucose are absorbed at the apical pole of the enterocyte by glucose transporter (GLUT) 5 and sodium-glucose co-transporter 1 (SGLT-1), respectively. The entry of fructose from the basolateral pole of the enterocyte is facilitated by GLUT5 and possibly GLUT2. Fructose uptake by the liver is primarily due to the action of GLUT2, but GLUT8 may also play a role in this process.

과당과 포도당은 

각각 포도당 수송체(GLUT) 5와 

나트륨-포도당 공동 수송체 1(SGLT-1)에 의해 

장세포의 정극에서 흡수됩니다.  

장세포의 기저극에서 과당의 유입은 

GLUT5와 GLUT2에 의해 촉진됩니다. 

간에서의 과당 흡수는 

주로 GLUT2의 작용에 의한 것이지만, 

GLUT8도 이 과정에서 중요한 역할을 할 수 있습니다.

FRUCTOSE METABOLISM: LESSONS LEARNED FROM HEREDITARY FRUCTOSE INTOLERANCE

HFI is an autosomal recessive disorder caused by a mutation in the gene-encoding aldolase B, the enzyme that converts F1P into glyceraldehyde (GA) and dihydroxyacetone phosphate (DHAP). GA is subsequently metabolized to pyruvate, which feeds the tricarboxylic acid (TCA) cycle via pyruvate dehydrogenase or is converted by lactate dehydrogenase to lactate. Through DHAP, fructose serves as a precursor for triglyceride synthesis via the intermediary metabolite glycerol-3-phosphate, which is conjugated to fatty acids generated by de novo lipogenesis (DNL) from citrate, exiting the TCA cycle (Figure 1), although bacterial acetate has also emerged as a lipogenic substrate (Zhao et al., 2020), which will be further discussed later on. In patients with HFI, F1P accumulates, leading to phosphate trapping and ATP depletion (Kim et al., 2021). The reduction in ATP and inorganic phosphate leads to uric acid accumulation in enterocytes, hepatocytes, and renal tubular cells, as well as lactic acidosis and hypokalemia, resulting in liver and kidney cell toxicity (Kim et al., 2021; Richardson et al., 1979). These metabolic disturbances are thought to be responsible for hepatic and renal dysfunction in patients with HFI (Richardson et al., 1979).

HFI는 

F1P를 글리세랄데히드(GA)와 

디하이드록시아세톤 인산염(DHAP)으로 전환하는 효소인 

알돌라제 B 유전자 코딩 돌연변이로 인해 발생하는 

상염색체 열성 질환입니다.  

이후 GA는 피루베이트 탈수소효소를 통해 트리카르복실산(TCA) 순환에 공급되는 피루베이트로 대사되거나 젖산 탈수소효소에 의해 젖산염으로 전환됩니다. DHAP를 통해 과당은 중간 대사산물인 글리세롤-3-인산염을 통해 중성지방 합성의 전구체 역할을 하며, 이는 구연산염에서 신생 지방 생성(DNL)에 의해 생성된 지방산에 접합되어 TCA 순환을 빠져나가지만(그림 1), 박테리아 아세테이트도 지방 생성 기질로 등장했습니다(Zhao et al., 2020), 이는 나중에 자세히 논의될 것입니다. 

HFI 환자에서는 

F1P가 축적되어 인산염 트래핑과 

ATP 고갈로 이어집니다(Kim et al., 2021). 

ATP와 무기 인산염의 감소는 

장세포, 간세포 및 신장 세뇨관 세포에 

요산 축적과 젖산증 및 저칼륨 혈증을 유발하여 

간 및 신장 세포 독성을 유발합니다 (Kim et al., 2021; Richardson et al., 1979). 

이러한 대사 장애는 

HFI 환자의 간 및 신장 기능 장애의 원인으로 생각됩니다 (Richardson et al., 1979).

Fructose intolerance has largely been viewed as a liver disease, rather than as a GI disease, and this may be due to the histopathology and ultrastructural presentation of liver biopsies from patients with HFI, which show giant cell transformation, steatosis, fibrosis, and even cirrhosis (Phillips et al., 1968). HFI livers also present with abnormal membrane-bound bodies in the areas of glycogen deposition, which have been termed as “fructose holes” (Phillips et al., 1970). In addition, patients with HFI present with NAFLD, which is not related to obesity and insulin resistance (Aldámiz-Echevarría et al., 2020). In fact, unlike most patients who present with NAFLD and with insulin resistance and/or hyperglycemia, HFI is an unusual cause of hypoglycemia (Morales-Alvarez et al., 2019), suggesting that, in addition to DNL, HFI-induced NAFLD may be caused by impaired mitochondrial function (Lanaspa et al., 2012). As with many genetic disorders, much can be learned by studying pre-clinical models that phenocopy human disease, as is the case with aldolase-B-deficient mice (Oppelt et al., 2015). Genetic ablation and pharmacological inhibition of the KHK-C isoform in aldolase-B-deficient mice prevented hypoglycemia and the liver and GI injuries associated with HFI (Lanaspa et al., 2018).

과당 불내증은 

주로 위장 질환이 아닌 

간 질환으로 간주되어 왔으며, 

이는 HFI 환자의 간 생검에서 

거대 세포 변형, 지방증, 섬유증, 간경변까지 보이는 

조직 병리학과 초구조적 소견 때문일 수 있습니다(Phillips et al., 1968). 

HFI 간은 또한 글리코겐 침착 부위에 비정상적인 막 결합체가 존재하며, 이를 '과당 구멍'이라고 부릅니다(Phillips 등, 1970). 또한, HFI 환자는 비만 및 인슐린 저항성과 관련이 없는 NAFLD를 동반합니다(Aldámiz-Echevarría et al., 2020). 

실제로 

인슐린 저항성 및/또는 

고혈당증을 동반하는 대부분의 환자들과 달리 

HFI는 저혈당의 특이한 원인이며(Morales-Alvarez 등, 2019), 

이는 DNL 외에도 HFI로 인한 NAFLD가 

미토콘드리아 기능 장애로 인해 발생할 수 있음을 시사합니다(Lanaspa 등, 2012). 

많은 유전 질환과 마찬가지로, 

알돌라제-B 결핍 생쥐의 경우처럼 

인간의 질병을 표현하는 전임상 모델을 연구함으로써 많은 것을 배울 수 있습니다(Oppelt et al., 2015). 

알돌라제-B 결핍 마우스에서 

KHK-C 동형체의 유전자 제거 및 약리학적 억제는 

저혈당증과 HFI와 관련된 간 및 위장관 손상을 예방했습니다(Lanaspa et al., 2018).

HFI diagnosis is usually made at an early age (~6 months) when infants are weaned off breast milk. Early symptoms include nausea, vomiting, and abdominal pain (Kim et al., 2021), the severity of which depends on the specific mutation in ALD-B, which resides on chromosome 9q22. The most common mutations are A150P, A149P, and A174D (Esposito et al., 2004; Lau and Tolan, 1999). HFI is treated mainly by dietary adherence and patients have an excellent prognosis if they follow strict dietary advice (Ahmad and Sharma, 2021), although the work discussed earlier (Lanaspa et al., 2018) suggests that KHK inhibitors may provide an alternative therapeutic option. In toto, although aldolase B is expressed in the liver, kidney, and GI tract, and patients with HFI eventually develop severe liver abnormalities, the initial defect may be due to intestinal aldolase B deficiency, as patients first present with recurrent vomiting, abdominal bloating, and diarrhea (Ahmad and Sharma, 2021).

HFI는 

일반적으로 영아가 모유를 끊는 초기(~6개월)에 진단합니다. 

초기 증상으로는 

메스꺼움, 구토, 복통 등이 있으며(Kim et al., 2021), 

그 심각성은 9q22 염색체에 존재하는 ALD-B의 특정 돌연변이에 따라 달라집니다. 

가장 흔한 돌연변이는 A150P, A149P 및 A174D입니다(Esposito et al., 2004; Lau and Tolan, 1999). 

HFI는 주로 식이 요법을 통해 치료하며 

환자가 엄격한 식이 요법을 준수하면 예후가 좋지만(Ahmad and Sharma, 2021), 

앞서 논의한 연구(Lanaspa 등, 2018)에 따르면 KHK 억제제가 대체 치료 옵션을 제공할 수 있다고 합니다. 

알돌라제 B는 간, 신장, 위장관 등에서 발현되고 HFI 환자는 결국 심각한 간 이상을 일으키지만, 환자가 처음에 반복되는 구토, 복부 팽만감, 설사 증상을 보이는 것처럼 초기 결함은 장의 알돌라제 B 결핍으로 인한 것일 수 있습니다(Ahmad and Sharma, 2021).

HEPATIC FRUCTOSE METABOLISM AND PATHOPHYSIOLOGY

Fructose is taken up via GLUT5 at the enterocyte apical pole, whereas glucose is absorbed via the sodium-glucose-linked transporter-1 (SGLT-1) (Ferraris et al., 2018) (Figure 2). How the two sugars are released into the portal circulation is controversial. Although some have proposed that GLUT2 facilitates release of both glucose and fructose at the enterocyte basolateral pole (Ferraris et al., 2018; Kellett and Helliwell, 2000), others have observed that GLUT2 has a lower affinity for fructose compared with GLUT5 (GLUT2: Km = 11.0 mM) (Manolescu et al., 2007). This suggests that GLUT2 is a minor contributor to fructose export from the GI tract, with the major basolateral transporter being GLUT5 (Hannou et al., 2018; Manolescu et al., 2007) (Figure 2). However, it is well accepted that fructose uptake into the liver is primarily mediated by GLUT2 (Cheeseman, 1993; Colville et al., 1993; Karim et al., 2012) because GLUT5 is not well expressed in this tissue (Karim et al., 2012). GLUT8 may also play a role in fructose uptake by the liver (Debosch et al., 2014) (Figure 2).

과당은 

장세포 정극에서 GLUT5를 통해 흡수되는 반면 

포도당은 나트륨-포도당 연결 수송체-1(SGLT-1)을 통해 흡수됩니다(Ferraris et al., 2018)(그림 2).  

두 당이 

어떻게 문맥 순환으로 방출되는지는 논란의 여지가 있습니다. 

일부에서는 GLUT2가 

장세포 기저극에서 포도당과 과당의 방출을 촉진한다고 제안했지만(Ferraris et al., 2018; Kellett and Helliwell, 2000), 

다른 연구자들은 GLUT2가 GLUT5에 비해 과당 친화성이 낮다는 것을 관찰했습니다(GLUT2: Km = 11.0 mM)(Manolescu et al., 2007). 

이는 GLUT2가 위장관으로부터 과당 배출에 부수적으로 기여하며, 

주요 기저측 수송체는 GLUT5임을 시사합니다(Hannou et al., 2018; Manolescu et al., 2007)(그림 2). 

그러나 

간으로의 과당 흡수는 

주로 GLUT2에 의해 매개된다는 것이 잘 알려져 있는데, 

이는 GLUT5가 이 조직에서 잘 발현되지 않기 때문입니다(Cheeseman, 1993; Colville et al., 1993; Karim et al., 2012). GLUT8은 또한 간에서 과당 흡수에 중요한 역할을 할 수 있습니다(Debosch et al., 2014)(그림 2).

Once fructose enters the cell, it is rapidly metabolized by KHK to F1P (Figure 1). Along with its high affinity for fructose, KHK also has a high Vmax (~3 μmol/min/g wet weight in rat liver) (Adelman et al., 1967). As such, the metabolism of fructose, once inside the hepatocyte, is rapid, following the same path as within the enterocyte, eventually giving rise to citrate, as a result of oxidative stress-induced inhibition of aconitase (Lambertz et al., 2017), the enzyme that catalyzes the stereo-specific isomerization of citrate to isocitrate via cis-aconitate. Citrate is converted by ATP citrate lyase (ACLY) to acetyl-CoA, which is converted by ACC1 to malonyl CoA, the precursor for fatty acid synthesis by fatty acid synthase (FASN). Upon conjugation with G3P, the C:16 and C:18 fatty acids made by FASN are converted to TAG (Figure 1), which forms lipid droplets. Excessive lipid droplet buildup within hepatocytes gives rise to NAFLD, which in response to additional hits progresses to NASH (Lyssiotis and Cantley, 2013; Vos and Lavine, 2013). The role of DNL in the generation of liver fat from fructose is unequivocal, since administration of 14C-fructose in rodents (Bar-On and Stein, 1968) or 13C-acetate together with fructose in humans (Parks et al., 2008) results in tracer incorporation into liver lipids. However, the role of ACLY in the fructose-driven NAFLD was recently questioned (Zhao et al., 2020), but as discussed further on, these results may not apply to NAFLD driven by long-term fructose consumption. However, it is also important to note that compared with glucose, fructose ingestion has a minor effect on plasma glucose and insulin, an important stimulator of fat storage. Moreover, a large fraction of ingested fructose is oxidized, with ~25% being converted to lactate and approximately 15%, giving rise to glycogen. Thus, compared with glucose, less ingested fructose is converted to triglycerides (Petersen et al., 2001; Tappy and Lê, 2010; Tappy et al., 1986).

과당이 세포에 들어가면 

KHK에 의해 F1P로 빠르게 대사됩니다(그림 1). 

과당에 대한 높은 친화성과 함께 

KHK는 높은 Vmax(쥐 간에서 ~3μmol/min/g 습윤 중량)를 가지고 있습니다(Adelman et al., 1967). 

따라서 

간세포 내에서 과당의 대사는 

장세포 내에서와 동일한 경로를 따라 빠르게 진행되며, 

산화 스트레스에 의한 아코니타제 억제(Lambertz et al., 2017)의 결과로 

구연산염이 시스아코니테이트를 통해 

이소구연산염으로 입체 특이적 이성질화되는 것을 촉매하는 효소인 

아코니타제가 억제되어 결국 구연산염이 생성됩니다. 

구연산염은 

ATP 구연산염 분해효소(ACLY)에 의해 아세틸-CoA로 전환되고, 

이는 지방산 합성 효소(FASN)에 의해 지방산 합성을 위한 전구체인 말로닐 CoA로 ACC1에 의해 전환됩니다. 

G3P와 결합하면 

FASN에 의해 만들어진 C:16 및 C:18 지방산이 TAG로 전환되어 지질 방울을 형성합니다(그림 1). 간세포 내에 과도한 지질 방울이 축적되면 NAFLD가 발생하고, 추가적인 공격에 반응하여 NASH로 진행됩니다

(Lyssiotis and Cantley, 2013; Vos and Lavine, 2013). 

설치류에 14C-과당을 투여하거나(Bar-On and Stein, 1968) 인간에게 과당과 함께 13C-아세테이트를 투여하면 추적자가 간 지질에 통합되기 때문에 과당에서 간 지방을 생성하는 데 DNL의 역할은 분명합니다(Parks et al., 2008). 그러나 최근 과당으로 인한 NAFLD에서 ACLY의 역할에 대한 의문이 제기되었지만(Zhao et al., 2020) 위에서 자세히 설명한 것처럼 이러한 결과는 장기 과당 섭취로 인한 NAFLD에는 적용되지 않을 수 있습니다. 그러나 포도당에 비해 과당 섭취는 지방 저장의 중요한 자극제인 혈장 포도당과 인슐린에 미치는 영향이 미미하다는 점도 주목할 필요가 있습니다. 또한 섭취한 과당의 상당 부분이 산화되어 약 25%는 젖산염으로, 약 15%는 글리코겐으로 전환됩니다. 따라서 포도당에 비해 섭취한 과당은 중성지방으로 전환되는 양이 적습니다(Petersen et al., 2001; Tappy and Lê, 2010; Tappy et al., 1986).

As obesity rates have grown in parallel with HFCS consumption, many researchers assume that HFCS and fructose consumption contribute to obesity (Bray et al., 2004). However, recent research suggests that this may not be the case. Although rodent studies suggest that fructose feeding induces leptin resistance, which leads to weight gain (Shapiro et al., 2008), in well-controlled human studies, a fructose-rich diet did not increase weight compared with a diet matched for energy from glucose (Stanhope et al., 2009). Further human studies have demonstrated that gut-derived appetite-controlling hormones, such as leptin and ghrelin, are not elevated by HFCS consumption (Melanson et al., 2007; Soenen and Westerterp-Plantenga, 2007). This has led both the American Medical Association and the Academy of Nutrition and Dietetics to conclude that HFCS is not a direct cause of obesity (Klurfeld et al., 2013). Nonetheless, the weight of evidence suggests that long-term and excessive fructose consumption results in dyslipidemia and hepatosteatosis (Tappy and Lê, 2010). As discussed earlier, it is extremely difficult to determine the effects of increased fructose intake per se on disease pathology because fructose is usually consumed in the diet as sucrose or HFCS, not as free fructose and studies often do not match for caloric content (Tappy and Lê, 2010), raising the possibility that disease pathology is simply a function of caloric excess.

This point has been addressed in a carefully controlled human study where overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of their energy requirements for 10 weeks (Stanhope et al., 2009). Importantly, hepatic DNL and postprandial triglyceride content were only increased in the group subjected to fructose (Stanhope et al., 2009). Several studies have demonstrated that a much larger fraction of ingested fructose fluxes into DNL relative to glucose (Crescenzo et al., 2013; Kazumi et al., 1986; Parks et al., 2008; Zavaroni et al., 1982). These pre-clinical studies have recently been verified in a randomized-controlled study in humans (Geidl-Flueck et al., 2021). The pathways by which fructose supports hepatosteatosis, DNL, and the generation of very low-density lipoprotein (VLDL) triglycerides were comprehensively discussed in previous reviews (Hannou et al., 2018; Tappy and Lê, 2010). Importantly, fructose enhances the expression‎ of sterol regulatory element-binding protein 1 (SREBP-1c), the major transcriptional regulator of the enzymes that mediate hepatic DNL (Matsuzaka et al., 2004; Shimomura et al., 1999; Softic et al., 2017). These results explain how fructose is associated with a poorer metabolic outcome compared with glucose ingestion (Softic et al., 2017). Fructose also affects the balance between fatty acid oxidation (FAO) and synthesis (DNL) by inhibiting the expression‎ of critical FAO-related enzymes (Lally et al., 2019; Pinkosky et al., 2020), including carnitine palmitoyltransferase1 (CPT1), which controls the entry of fatty acids into the mitochondria (Bruce et al., 2009; Goedeke et al., 2018) (Figure 1). Of note, CPT1 activators and ACC1 inhibitors are currently in clinical trials for the treatment of metabolic diseases (Goedeke et al., 2018; Schreurs et al., 2010; Softic et al., 2017), whereas bempedoic acid (Nexletol), an ACLY inhibitor, is a clinically approved drug to treat hypercholesterolemia, as it lowers LDL cholesterol and attenuates atherosclerosis (Pinkosky et al., 2016).

Work from our groups (Nakagawa et al., 2014; Todoric et al., 2020) and others (Kammoun et al., 2009; Lee et al., 2008) has demonstrated that fructose can induce endoplasmic reticulum (ER) stress, which, in turn, can drive hepatosteatosis (Nakagawa et al., 2014). The underlying pathway seems to involve caspase-2, whose expression‎ is inflammation (TNF) and ER stress inducible and leads to SCAP-independent activation of SREBP1/2 through non-canonical proteolytic activation of site 1 protease (S1P) (Kim et al., 2018). Interestingly, adipose tissue lipolysis has been suggested to contribute to NASH pathology (Thörne et al., 2010). However, paradoxically, acute fructose ingestion is antilipolytic (Abdel-Sayed et al., 2008; Tappy et al., 1986), suggesting that fructose does not promote adipose tissue lipolysis, which is consistent with the general observation that fructose consumption per se does not result in increased adiposity.

RECENT ADVANCES IN FRUCTOSE-INDUCED HEPATOSTEATOSIS

Until recently, fructose was thought to stimulate hepatosteatosis through liver-specific mechanisms. However, some years ago, Johnson and colleagues proposed that KHK in the GI tract could promote steatohepatitis in horses (Johnson et al., 2013) and humans (Jensen et al., 2018). This hypothesis was tested in mice by specifically ablating KHK in the intestine and/or liver (Andres-Hernando et al., 2020). Interestingly, intestinal-specific KHK deletion affected sugar intake and preference, causing an aversion type of response to fructose. These recent results are consistent with previous observations in whole-body A and C isoform KHK-deficient mice who, unlike their wild-type counterparts, did not show preference for fructose-sweetened water over water alone (Ishimoto et al., 2012). However, critically, intestinal-specific KHK deletion did not prevent hepatosteatosis (Andres-Hernando et al., 2020). In contrast, hepatocyte-specific KHK ablation prevented both hepatosteatosis and metabolic disease (Andres-Hernando et al., 2020). Recent work from several laboratories, including ours, also suggests that fructose affects hepatosteatosis through the “gut-liver axis,” a physiological circuit through which gut microbiota and/or their products reach the liver via the portal circulation to provoke an inflammatory response that alters liver metabolism. Although it may seem that fructose-induced liver pathology through a link between the gut and the liver is a relatively new concept, this physiological link has been known for some time. In 1969, Blendis and colleagues (Blendis et al., 1969) first described the coeliac axis and its impact on liver disease. This was not entirely surprising, since the gut and the liver are connected via the portal circulation that drains digested food and components of disintegrated bacteria into the liver. The concept that the gut affects liver disease is supported by observations that are as follows: (1) the liver is the primary site for colon cancer metastasis, (2) steatohepatitis frequently develops in patients with jejunoileal bypass and short bowel syndrome, and (3) many viral, bacterial, fungal, and parasitic diseases affect the intestine, as well as the liver and the biliary tract (Zeuzem, 2000). In a key paper published in 2006, Gordon and colleagues identified the gut microbiome as a pivotal player in the etiology of obesity-related metabolic disease (Turnbaugh et al., 2006). With this observation, the gut microbiome became a part of the gut-liver axis and a target for treatment of numerous metabolic diseases affecting the liver, discussed in detail subsequently. Moreover, hepatosteatosis and NAFLD are common co-morbidities of inflammatory bowel disease (Chao et al., 2016).

In a recent study conducted by Wellen, Rabinowitz, and coworkers (Zhao et al., 2020), ACLY was specifically ablated in mouse hepatocytes. Using in vivo isotopic tracing, the authors found that this genetic manipulation did not prevent fructose-induced hepatosteatosis, although it should be noted that, in this study, the high-fructose diet did not markedly increase hepatic triglyceride content even in wild-type control mice (Zhao et al., 2020). The same authors previously observed that fructose is converted to acetate by the microbiota (Jang et al., 2018) and that acetate can generate acetyl-CoA independent of ACLY (Zhao et al., 2016). Accordingly, they tested the hypothesis that fructose-induced lipogenesis in the liver is driven by microbiota-derived acetate. They observed that the depletion of microbiota markedly suppressed the conversion of fructose into acetyl-CoA in the liver and hepatosteatosis (Zhao et al., 2020), suggesting that fructose metabolism in the GI tract may control hepatosteatosis (Figure 3). However, as discussed below, any experiment based on bulk depletion of the microbiota needs to be carefully interpreted because of the major role of Gram-negative gut bacteria in the generation of endotoxin (LPS), which seems to be a key player in fructose-induced hepatosteatosis (Todoric et al., 2020). Moreover, all bacteria release bacterial nucleic acids that further enhance hepatic inflammation. In a recent study (Jang et al., 2020), the Rabinowitz group performed intestinal-specific KHK-C (the more active KHK isozyme) loss- and gain-of-function experiments. They demonstrated that, on the one hand, KHK-C deletion increased fructose delivery to the liver and that the microbiota promoted hepatosteatosis (Jang et al., 2020). On the other hand, KHK-C overexpression‎ decreased fructose-induced lipogenesis (Jang et al., 2020). The authors concluded that metabolism of fructose in the gut shields the liver from fructose-induced fatty liver (Figure 3). Arriving at the same general conclusion, but via a different mechanism, our team found that fructose-induced hepatosteatosis is controlled by the intestinal epithelial barrier via the gut-liver axis (Todoric et al., 2020). Consistent with previous reports in animals (Cho et al., 2021; Kavanagh et al., 2013; Spruss et al., 2012) and humans (Jin et al., 2014), we found that excessive fructose consumption resulted in barrier deterioration, dysbiosis, low-grade intestinal inflammation, and endotoxemia (Todoric et al., 2020). Although we attributed barrier deterioration to KHK-dependent conversion of fructose to F1P in enterocytes, the protective effect of intestinal KHK-C ablation suggests that fructose-induced microbial dysbiosis may be the primary driver of barrier deterioration. Indeed, microbial depletion with antibiotics leads to a partial reversal of fructose-induced barrier deterioration (Todoric et al., 2020). Using RNA sequencing, we confirmed the presence of an endotoxin-induced transcriptional signature defined by the marked upregulation of toll-like receptors (TLR) 2,3,4,6,7, and 8, and their adaptor protein MyD88, and the induction of inflammatory chemokines and cytokines, such as CCL2, CCL5, and TNF, in the livers of fructose-fed mice (Todoric et al., 2020). Similarly, Spruss and coworkers found that TLR4-deficient mice were protected from fructose-induced NAFLD (Spruss et al., 2009). Using several different approaches, including intestinal-specific expression‎ of the antimicrobial protein Reg3b and myeloid-specific MyD88 ablation, we provided further support for the role of endotoxin and other microbial-generated inflammatory signals in the enhancement of fructose-induced DNL and hepatosteatosis (Todoric et al., 2020). This occurs through a multicomponent pathway consisting of recruited hepatic macrophages that produce TNF (Figure 3), which, by engaging its type 1 receptor (TNFR1) on hepatocytes, leads to the induction of the critical lipogenic enzymes ACLY, ACC1, and FASN, which convert fructose-derived acetyl-CoA to C16 and C18 fatty acids (Todoric et al., 2020). Consistent with our previous demonstration that TNFR1 signaling blockade prevents NASH (Febbraio et al., 2019; Kim et al., 2018), we found that incubation of human hepatocytes with TNF also results in the induction of lipogenic enzyme mRNAs and the conversion of either fructose or glucose to lipid droplets (Todoric et al., 2020). Critically, fructose, but not cornstarch (glucose), isocaloric feeding led to the downregulation of enterocyte tight-junction proteins and subsequent barrier deterioration, which is in agreement with previous rodents and human studies (Jin et al., 2014; Kavanagh et al., 2013; Lambertz et al., 2017; Spruss et al., 2012). In the past (Taniguchi et al., 2015), we found that enterocyte IL-6 signaling stimulates epithelial cell proliferation through the activation of Yes-associated protein (YAP), thereby conferring resistance to mucosal erosion. To test whether YAP activation can prevent fructose-induced inflammation, hepatosteatosis, and NASH, we expressed an activated form of IL-6 signal transducer (IL6ST), also known as gp130, exclusively in enterocytes, or injected fructose-fed mice with the YAP-induced matricellular protein cellular communication network factor 1 (CCN1). Both manipulations prevented the downregulation of tight-junction proteins, endotoxemia, and ameliorated fructose-induced hepatosteatosis, and NASH (Todoric et al., 2020). Although most of the studies mentioned earlier confirm‎ the importance of the enterocyte in regulation of liver fructose metabolism, due to different experimental conditions, they arrive at seemingly different conclusions. Rabinowitz and colleagues (Jang et al., 2020), using comparatively low amounts of fructose, found that enterocyte-specific KHK-C deficiency was not protective, but hepatic steatosis was quite low in these experiments, as also observed previously (Zhao et al., 2020). Using higher amounts of fructose that cause barrier deterioration, we suggested that accumulation of toxic F1P within enterocytes may initiate the inflammatory cascade underlying hepatic steatosis and predicted that KHK inhibition should be protective (Todoric et al., 2020), which has been subsequently demonstrated (Gutierrez et al., 2021). However, as discussed earlier, the protective effect of KHK inhibition is mainly manifested in the liver and instead of F1P-induced toxicity, barrier deterioration is probably due to dysbiosis. Notably, fructose-induced inflammation is only observed after prolonged exposure, and its magnitude may depend on the animal facility, a variable that profoundly affects the microbiota (Ussar et al., 2015). Indeed, given the critical pathogenic role of barrier deterioration and endotoxemia, there is little doubt that the microbiota is a key contributor to fructose-induced liver disease (Jadhav and Cohen, 2020).

Figure 3.

Schematic summary of proposed mechanisms for fructose-induced hepatosteatosis via the gut-liver axis

Excess fructose consumption can lead to altered microbiota and the production of short chain fatty acids that ultimately stimulate hepatosteatosis. Fructose can also disrupt gut barrier integrity, resulting in systemic endotoxemia, leading to the activation of an inflammatory cascade via macrophage toll-like receptor 4 (TLR4) signaling, thus resulting in tumor necrosis factor (TNF)-induced hepatosteatosis.

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THERAPEUTIC TARGETS FOR FRUCTOSE-INDUCED STEATOHEPATITIS

NASH is one of the fastest growing metabolic diseases and has become the leading cause of liver transplantation in the USA. Not surprisingly, the NASH drug market is estimated to reach $40 billion (USD) by 2025 (Febbraio et al., 2019). Currently, there are over 30 clinical trials of new NASH drug candidates, as previously discussed by us (Febbraio et al., 2019; Smeuninx et al., 2020) and others (Lazaridis and Tsochatzis, 2017). Most therapeutic approaches to NAFLD and NASH have focused on pathways that affect the balance between fatty acid uptake and export, DNL, and FAO, as well as liver fibrosis. However, disappointingly, this therapeutic strategy has been associated with untoward side effects. Two of the most advanced drug candidates are the farnesoid X nuclear receptor (FXR) ligand obeticholic acid (Ocaliva; Intercept Pharmaceuticals) and the dual peroxisome proliferator activated receptor (PPAR)α/δ agonist GFT505 (Elafibranor: Genfit), which have both reached phase III clinical trials. Another NASH drug candidate is MK-4074, a liver-specific ACC1/2 inhibitor. Although a 1-month treatment course was effective in reducing lipogenesis and liver TAG by >30%, MK-4074 unexpectedly increased plasma triglycerides by 200% (Kim et al., 2017a). Likewise, Ocaliva was rejected by the FDA in July 2020, owing to elevated LDL cholesterol in a significant number of patients. Given the common issue of hyperlipidemia and hypercholesterolemia, new therapeutic strategies are warranted. Recently, Gilead released the results from the 392-patient ATLAS study, which tested Firsocostat, an ACC inhibitor, and Cilofexor, another FXR agonist, alone and in combination. In patients with bridging fibrosis and cirrhosis, 48 weeks of Cilofexor/Firsocostat was well tolerated and led to improvements in NASH activity but did not meet the antifibrotic target to conclude that the trial was successful (Loomba et al., 2021). Pfizer has also developed PF-05221304, an orally bioavailable, liver-directed ACC1/2 inhibitor. Recently, it was found to improve multiple NASH markers, including steatosis, inflammation, and fibrosis in both human primary hepatocytes and rats in vivo (Ross et al., 2020). It is currently undergoing human clinical trials (Bergman et al., 2020). As discussed earlier, the genetic deletion of KHK-C in hepatocytes (Andres-Hernando et al., 2020) can prevent hepatosteatosis and metabolic disease in mice, raising the possibility that KHK inhibition may be a viable therapeutic strategy. Recently, Pfizer has developed the KHK inhibitor PF-06835919, which is showing promise as a drug to treat NASH. In a recent study, this drug was tested in both primary hepatocytes and fructose-fed rats. PF-06835919 prevented hyperinsulinemia and hypertriglyceridemia, and reduced DNL (Gutierrez et al., 2021). Encouragingly, the authors reported the inhibitor to be safe and well tolerated in healthy humans, albeit after a single dose (Gutierrez et al., 2021). The drug is currently in a phase 2A trial in patients with NAFLD (ClinicalTrials.gov identifier: NCT03256526). However, of concern are the mouse studies showing that intestinal KHK deletion increased fructose delivery to the liver via spillover from the portal circulation (Andres-Hernando et al., 2020; Jang et al., 2020). Therefore, pan KHK inhibitors may present unwanted side effects, particularly when fructose ingestion is an important driver of NASH development.

Given the conflicting outcomes of KHK deletion in the gut versus the liver, we posit that new treatments for fructose-driven NASH should focus on preventing inflammation, ER stress, and gut barrier deterioration. We (Nakagawa et al., 2014; Todoric et al., 2020) and others (Kammoun et al., 2009; Lee et al., 2008) have demonstrated that fructose can lead to enterocyte ER stress, giving rise to barrier deterioration. Accordingly, the administration of ER-stress-inhibiting chemical chaperones, such as tauroursodeoxycholic acid (TUDCA), a bile acid that is found in trace amounts in humans, but is quite abundant in black bears, was effective in preventing NAFLD-NASH in mice (Nakagawa et al., 2014; Todoric et al., 2020). TUDCA is sold as a nutritional supplement, but so far, it has only been used to treat primary biliary cholangitis, where it was found to be safe and effective (Ma et al., 2016). Recently, TUDCA and another chemical chaperone, phenylbutyrate (PB), were the subjects of a multicenter, randomized double-blinded clinical trial to test their safety and efficacy in amyotrophic lateral sclerosis (ALS) (Paganoni et al., 2020). Although the treatment resulted in slower functional decline than placebo, adverse GI events were noted (Paganoni et al., 2020). In recent, but important studies, evidence from the Randolph laboratory (Han et al., 2021) suggests that high-density-lipoprotein (HDL)-raising drugs may also be a therapeutic option for preventing gut-mediated liver injury. These authors demonstrated that the production of HDL by enterocytes protected the liver from gut-derived LPS leakage in both NASH and alcoholic steatohepatitis (ASH).

Other important components of NAFLD-NASH pathogenesis, whose expression‎ by infiltrating macrophages and resident Kupffer cells is induced subsequently to barrier deterioration are inflammatory cytokines such as IL-6 and TNF (Nakagawa et al., 2014; Naugler et al., 2007; Park et al., 2010). The inhibition of TNF signaling prevents NAFLD and NASH in mice (Wandrer et al., 2020) and TNF stimulates lipid droplet accumulation in human hepatocytes (Todoric et al., 2020), suggesting that TNF inhibition is a viable therapeutic strategy. The effect of TNF inhibitors on ASH and NASH in patients treated for auto-inflammatory diseases was examined and the results were mixed (Spahr et al., 2002; Tang et al., 2020; Zein et al., 2011; Zein and Etanercept Study Group, 2005). The selective activation of IL-6 signaling is more complex, as it can enhance the development of colorectal and liver cancers (Greten et al., 2004; Naugler et al., 2007). Therefore, we have undertaken a novel approach to generate selective IL-6 inhibitors that only block adverse IL-6 signaling and mimics that lack some of the negative effects of IL-6 itself. One such agent, sgp130 (Olamkicept), is a biologic that targets “IL-6 trans-signaling,” the component of IL-6 signaling that causes inflammation (Febbraio et al., 2010). Olamkicept is currently in a phase II clinical trial for the treatment of ulcerative colitis (Schreiber et al., 2021), but we propose that this drug may also have therapeutic utility in NASH because in pre-clinical studies, we found that treating diet-induced obese mice with sgp130Fc ameliorates liver inflammation (Kraakman et al., 2015). Accordingly, we are currently pursuing studies in our mouse model of NASH. The selective blockade of trans-signaling has merit because activation of the membrane-bound IL-6 receptor can be beneficial for metabolic diseases, including NASH, due to barrier repair (Taniguchi et al., 2015; Todoric et al., 2020) and the activation of AMPK (Carey et al., 2006), further reducing hepatic steatosis (Matthews et al., 2010). Therefore, drugs that block the trans-signaling component of IL-6 but activate the membrane-bound IL-6R signaling, are desirable for treating metabolic disease. Accordingly, we developed IC7Fc, a chimera of IL-6 and a related cytokine, cliliary neurotrophic factor (CNTF), which stimulates protective gp130 signaling, but cannot induce IL-6 trans-signaling, because it requires a different tripartite signaling complex compared with IL-6 (Findeisen et al., 2019). IC7Fc prevented high-fat-diet-induced insulin resistance and NAFLD, while preserving muscle mass through YAP activation (Findeisen et al., 2019). We are currently eval‎uating whether IC7Fc activates YAP in enterocytes and can thereby improve GI barrier function and prevent NASH, in addition to its ability to prevent NAFLD (Findeisen et al., 2019). However, it should be noted that, in certain circumstances, the activation of YAP may enhance colonic adenocarcimas in mice (Deng et al., 2018); therefore, drugs that directly and indiscriminately activate YAP may have limited therapeutic utility. Of note, Lau and coworkers have shown that systemic treatment with the YAP-induced protein CCN1 can enhance protective IL-6 signaling and ameliorate detran sodium sulfate (DSS)-indexed colitis in mice (Choi et al., 2015). These effects of CCN1 were incredibly similar to those of enterocyte-specific gp130 activation (Taniguchi et al., 2015) described earlier. Accordingly, we gave CCN1 to fructose-fed mice and found that it inhibited intestinal inflammation, endotoxemia, and NAFLD-NASH (Todoric et al., 2020). Therefore, these data suggest that targeting CCN1 downstream of YAP is a more viable therapeutic approach.

Other ways to enforce barrier function include the administration of an IL-22-Fc fusion protein (Shohan et al., 2020) and the induction of IL-22 expression‎ with aryl hydrocarbon receptor (AhR) agonists (Yang et al., 2020). IL-22 is a unique cytokine produced by type 2 innate lymphoid cells (ILC2) that acts on epithelial cells located at barrier surfaces. Studies conducted by Stockinger and coworkers have demonstrated that, under certain circumstances, IL-22 can prevent barrier disruption and protect against liver pathologies (Ahlfors et al., 2014; Mastelic et al., 2012; Turner et al., 2013). Others have shown that by stimulating intestinal stem cell proliferation, IL-22 maintains barrier integrity during graft versus host disease (Lindemans et al., 2015). Non-toxic AhR agonists that induce IL-22 production by ILC3 cells also maintain barrier integrity (Duarte et al., 2013; Schiering et al., 2018; Stockinger et al., 2009; Veldhoen et al., 2009; Yang et al., 2020).

As discussed earlier, the gut microbiota is another key component of the gut-liver axis that may play a cardinal, but poorly understood and complex, role in NAFLD-NASH pathogenesis and therefore may provide novel therapeutic opportunities. The concept that probiotics may be useful in NASH treatment was the subject of an extensive review (Lirussi et al., 2007). Preliminary data from two pilot, non-randomized studies suggested that probiotics may be well tolerated, may improve conventional liver function, and may decrease markers of lipid peroxidation. However, the 2007 review concluded that because these clinical trials were not well controlled, it was impossible to support or refute the use of probiotics in NASH. This is not unexpected because the gut microbiota is highly complex, consisting of thousands of different species, some of which are protective, whereas others are facultative pathogens. In addition to systemic endotoxemia (Schreurs et al., 2010) and production of acetate (Zhao et al., 2020), the microbiota is responsible for the generation of secondary bile acids that can have profound effects on liver physiology (Jadhav and Cohen, 2020; Zeng et al., 2020). Recently, the bacterial genus Clostridium was found to be markedly elevated in mice with NASH, resulting in low circulating glycine (Rom et al., 2020), which is associated with insulin resistance and hepatosteatosis (Newgard et al., 2009). Accordingly, Chen and colleagues (Rom et al., 2020) developed a glycine and leucine tripeptide, termed as DT109, whose administration to mice with NASH decreased Clostridium, increased glycine accumulation and attenuated hepatosteatosis. In addition, in a human NASH phase 2 clinical trial, Alderfermin, an engineered fibroblast growth factor 19 analog, which is secreted from the ileum in response to FXR activation and can suppress bile acid activity (Zhou et al., 2014), reduced liver fat with a mild improvement in fibrosis (Harrison et al., 2021). Interestingly, in a recent study, fecal microbiota transplantation from healthy, young vegan donors into patients with obesity and NASH resulted in a change in intestinal microbiota composition, which was associated with beneficial changes in plasma metabolites and markers of NASH (Witjes et al., 2020). Taken together, these findings suggest that microbiota modulation is a promising future approach to NASH treatment and prevention of fructose-induced steatosis. However, the enormous complexity of the gut microbiota requires rigorously controlled additional studies.

FRUCTOSE AND CARDIOVASCULAR DISEASE (CVD)

There is convincing evidence that high fructose intake can increase CVD risk. This may be due, in part, to fructose-enhanced hypertension (Hwang et al., 1987; Hwang et al., 1989). Rodent studies have suggested that this may depend on increased sympathetic activity, accumulation of glyceraldehyde and dihydroxyacetone phosphate, or a fructose-induced magnesium and/or copper deficiency (Tappy and Lê, 2010). It was also proposed that fructose induces hyperuricemia and that this may not only result in hypertension but can also increase gout preval‎ence (Ayoub-Charette et al., 2019; Johnson et al., 2003). Finally, high fructose intake was suggested to increase jejunal water and sodium chloride absorption through the transporters Slc26a6 and Slc2a5 (Singh et al., 2008). Irrespective of the mechanism, large human cohort studies show that high fructose consumption can increase CVD risk. This was examined in the Framingham Heart Study (6,039 people; mean age 52.9 years), in which participants were free of baseline metabolic syndrome. In this study, high soft drink consumption increased multiple CVD risk factors (Dhingra et al., 2007). Similarly, in a more recent study using the Jackson-Heart study data of African Americans, the consumption of HFCS in soda or fruit drinks (≥3 drinks per day) significantly increased CVD risk (DeChristopher et al., 2020). Although females were somewhat protected compared with men, the Nurse Health study of over 88,000 women also demonstrated that regular consumption of fructose in the form of soft drinks is associated with a higher CVD risk, even after other unhealthful lifestyle or dietary factors were accounted for (Fung et al., 2009).

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FRUCTOSE AND CANCER

HFCS consumption, rates of obesity and T2DM, and the incidence of some cancers have increased in parallel during the past 50 years (Currie et al., 2012; Genkinger et al., 2011; Nakagawa et al., 2020). Therefore, it has been difficult to determine whether excessive fructose consumption directly affects cancer. However, several lines of evidence point to fructose being a tumor promoter. First, fructose is absorbed by GLUT5 (Figure 2), and several studies found that GLUT5 is highly expressed in a variety of cancer cell lines (Harris et al., 1992; Mahraoui et al., 1992; Zamora-León et al., 1996). An association between fructose and cancer seems to be most relevant to pancreatic cancer, as suggested by large human associative studies (Hui et al., 2009; Larsson et al., 2006; Michaud et al., 2002; Schernhammer et al., 2005). More recently (Nakagawa et al., 2020), fructose intake was found to be associated with lung adenocarcinoma, myeloma, breast cancer, and glioma, primarily due to aberrant GLUT5 expression‎ and or activity. Recent research conducted by us (Nakagawa et al., 2014; Todoric et al., 2020) and others (Goncalves et al., 2019) demonstrated that high fructose consumption can promote liver and colorectal tumorigenesis. Remarkably, feeding miniscule amounts of fructose to adenomatous polyposis coli (APC)-mutant mice, which are predisposed to intestinal tumors, markedly increased tumor size and grade, independent of obesity or metabolic syndrome (Goncalves et al., 2019). The mechanism by which fructose acts in this system remains to be identified, as FASN ablation used by the authors can have a general effect on cell viability (Tanosaki et al., 2020). Using the MUP-uPA mouse model of NASH-driven hepatocellular cellular carcinoma (HCC), we demonstrated that consumption of a high-fructose diet led to HCC development independent of obesity (Todoric et al., 2020). However, HCC induction may not be due to a direct effect of fructose on the hepatocyte, as it was completely inhibited when the mice were treated with either broad-spectrum antibiotics or barrier-reinforcing agents (Todoric et al., 2020). Another mechanism by which fructose consumption can enhance HCC development is the induction of liver fibrosis associated with increased production of TGF-β and IL-21 that convert naive B cells to immunosuppressive IgA+ plasma cells, which also accumulate in the livers of patients with NASH (Shalapour et al., 2017). Through the expression‎ of IL-10 and PD ligand 1 (PD-L1), IgA+ plasma cells dismantle hepatic immunosurveillance mediated by CD8+ cytotoxic T cells (CTL). This can be avoided either by IgA+ plasma cell depletion or by treating the mice with a neutralizing PD-L1 antibody (Shalapour et al., 2017), which was proven to be effective in human HCC (El-Khoueiry et al., 2017).

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CONCLUSIONS

It has become increasingly clear that the excessive consumption of sugar-sweetened beverages and HFCS has contributed to the escalating incidence of metabolic diseases, such as T2D, NASH, CVD, and certain cancers. Although the underlying mechanisms are just being elucidated and the relevance of small animal models is being debated, it is obvious that fructose-induced liver diseases depend on a multicomponent pathogenic cascade. Although an altered liver lipid metabolism is the endpoint for this cascade, recent evidence has highlighted the importance of fructose-induced alterations in GI physiology, including barrier deterioration and dysbiosis. The downward self-amplifying spiral triggered by fructose may also apply to other disease-provoking macronutrients, such as excess fat or cholesterol. Recognizing the importance of the microbiota, gut barrier disruption, and systemic inflammation in fructose-induced NAFLD-NASH has opened the doors to new therapeutic interventions with these common, but difficult to treat, lifestyle-related diseases.

설탕이 첨가된 음료와 

HFCS의 과도한 섭취가 

T2D, NASH, CVD 및 특정 암과 같은 대사성 질환의 발병률 증가에 기여한다는 사실이 

점점 더 분명해지고 있습니다.  

근본적인 메커니즘이 이제 막 밝혀지고 있고 

소규모 동물 모델의 관련성에 대해 논의 중이지만, 

과당으로 인한 간 질환이 여러 가지 병원성 캐스케이드에 의존한다는 것은 분명합니다. 

간 지질 대사의 변화가 

이 캐스케이드의 종착점이지만, 

최근의 증거에 따르면 장벽 저하와 장내 미생물 이상증 등 

과당으로 인한 위장관 생리학의 변화가 중요하다는 사실이 강조되고 있습니다. 

과당에 의해 촉발된 하향 자기 증폭 나선은 

과도한 지방이나 콜레스테롤과 같은 

다른 질병을 유발하는 다량 영양소에도 적용될 수 있습니다. 

과당으로 인한 

NAFLD-NASH에서 미생물총, 

장 장벽 파괴 및 전신 염증의 중요성을 인식함으로써 

이러한 흔하지만 치료하기 어려운 생활 습관 관련 질병에 대한 새로운 치료 개입의 문이 열렸습니다.

ACKNOWLEDGMENTS

M.A.F. is a Senior Principal Research Fellow at the NHMRC (APP1116936) and is also supported by an NHMRC Investigator Grant (APP1194141). Research in his laboratory was supported by project grants from the NHMRC (APP1042465, APP1041760, and APP1156511 to M.A.F. and APP1122227 to M.A.F. and M.K.). M.K. is an American Cancer Research Society Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases. His research was supported by grants from the NIH (P42ES010337, R01DK120714, R01CA198103, R37AI043477, R01CA211794, and R01CA234128).

DECLARATION OF INTERESTS

M.K. holds US Patent No. 10034462 B2 on the use of MUP-uPA mice for the study of NASH and NASH-driven HCC. M.A.F. is a co-inventor of IC7Fc and hold patents for this molecule (US 60/920,822; WO/2008/119110 A1).

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