ChREBP refines the hepatic response to fructose to protect the liver from injury

Hall, A. Rupert; Finck, Brian N.

doi:10.1172/jci95008

Cited by 7 publications

(4 citation statements)

References 25 publications

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“…Third, FA binding protein 4 (FABP4)-Cre mediated expression of constitutively active ChREBP in mice was shown to improve insulin sensitivity and glucose tolerance in response to HFD challenge [74] . Finally, very recent studies demonstrated that ChREBP protected the liver from fructose-induced injury [75,76] . We recently found that both curcumin and insulin stimulated ChREBPα transcription via Akt-independent activation of MEK/ERK signaling, leading to the inactivation of the transcriptional repressor Oct-1 [77] .…”

Section: Both Curcumin and Insulin Stimulate Hepatic Chrebp Expressionmentioning

confidence: 99%

Curcumin and dietary polyphenol research: beyond drug discovery

Jin

2018

Acta Pharmacol Sin

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Numerous natural products available over the counter are commonly consumed by healthy, sub-healthy or ill people for the treatment and prevention of various chronic diseases. Among them, a few dietary polyphenols, including the curry compound curcumin, have been attracting the most attention from biomedical researchers and drug developers. Unlike many so-called "good drug candidates", curcumin and several other dietary polyphenols do not have a single known therapeutic target or defined receptor. In addition, the bioavailability of these polyphenols is usually very low due to their poor absorption in the gut. These recently debated features have created enormous difficulties for drug developers. In this review, I do not discuss how to develop curcumin, other dietary polyphenols or their derivatives into pharmaceutical agents. Instead, I comment on how curcumin and dietary polyphenol research has enriched our knowledge of insulin signaling, including the presentation of my perspectives on how these studies will add to our understanding of the famous hepatic insulin function paradox.

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Section: Both Curcumin and Insulin Stimulate Hepatic Chrebp Expressionmentioning

confidence: 99%

Curcumin and dietary polyphenol research: beyond drug discovery

Jin

2018

Acta Pharmacol Sin

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“…Notably, in the absence of ChREBP, high-fructose diets do not cause hepatic lipid accumulation, but inflammation and early signs of fibrosis instead [ 68 ]. It thus seems that ChREBP-mediated lipogenesis is required to prevent even more adverse hepatotoxicity upon fructose consumption, but that this adaptive mechanism may cause hepatic steatosis when too much fructose is consumed [ 69 ]. Increased hepatic ChREBP expression is also associated with NAFLD and insulin resistance in obese humans [ 70 ], but a direct effect of ingested fructose on ChREBP in human liver has not yet been demonstrated.…”

Section: What Are the Mechanisms Linking Fructose To Nafld?mentioning

confidence: 99%

Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease

Horst¹,

2017

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Increased fructose consumption has been suggested to contribute to non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, but a causal role of fructose in these metabolic diseases remains debated. Mechanistically, hepatic fructose metabolism yields precursors that can be used for gluconeogenesis and de novo lipogenesis (DNL). Fructose-derived precursors also act as nutritional regulators of the transcription factors, including ChREBP and SREBP1c, that regulate the expression of hepatic gluconeogenesis and DNL genes. In support of these mechanisms, fructose intake increases hepatic gluconeogenesis and DNL and raises plasma glucose and triglyceride levels in humans. However, epidemiological and fructose-intervention studies have had inconclusive results with respect to liver fat, and there is currently no good human evidence that fructose, when consumed in isocaloric amounts, causes more liver fat accumulation than other energy-dense nutrients. In this review, we aim to provide an overview of the seemingly contradicting literature on fructose and NAFLD. We outline fructose physiology, the mechanisms that link fructose to NAFLD, and the available evidence from human studies. From this framework, we conclude that the cellular mechanisms underlying hepatic fructose metabolism will likely reveal novel targets for the treatment of NAFLD, dyslipidemia, and hepatic insulin resistance. Finally, fructose-containing sugars are a major source of excess calories, suggesting that a reduction of their intake has potential for the prevention of NAFLD and other obesity-related diseases.

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“…Intriguingly, the insulin resistance state reversed in a mouse model of diabetes and insulin resistance (i.e., ob / ob mice) when ChREBP was downregulated [ 58 , 68 ]. Although inhibiting ChREBP decreases DNL caused by fructose and elevates TAG levels [ 69 ], it has been linked to adverse effects such as fructose intolerance, gastrointestinal distress including diarrhea and irritable bowel syndrome, as well as cholesterol-induced liver damage [ 69 , 70 , 71 , 72 ]. When adenoviral overexpression of ChREBP is induced in mice, intrahepatic triglyceride (IHTG) levels increased, the degree of steatosis advanced, but insulin action and glucose tolerance improved [ 59 ].…”

Section: Lipid Synthesis In Masldmentioning

confidence: 99%

Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease (MASLD)

Syed-Abdul

2023

Metabolites

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Metabolic-associated steatotic liver disease (MASLD) is a cluster of pathological conditions primarily developed due to the accumulation of ectopic fat in the hepatocytes. During the severe form of the disease, i.e., metabolic-associated steatohepatitis (MASH), accumulated lipids promote lipotoxicity, resulting in cellular inflammation, oxidative stress, and hepatocellular ballooning. If left untreated, the advanced form of the disease progresses to fibrosis of the tissue, resulting in irreversible hepatic cirrhosis or the development of hepatocellular carcinoma. Although numerous mechanisms have been identified as significant contributors to the development and advancement of MASLD, altered lipid metabolism continues to stand out as a major factor contributing to the disease. This paper briefly discusses the dysregulation in lipid metabolism during various stages of MASLD.

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ChREBP refines the hepatic response to fructose to protect the liver from injury

Abstract: "ChREBP refines the hepatic response to fructose to protect the liver from injury

Cited by 7 publications

References 25 publications

Curcumin and dietary polyphenol research: beyond drug discovery

Curcumin and dietary polyphenol research: beyond drug discovery

Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease

Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease (MASLD)

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