Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis

Shepherd, Emma L.; Saborano, Raquel; Northall, Ellie N.; Matsuda, Kae; Ogino, Hitomi; Yashiro, Hiroaki; Pickens, Jason; Feaver, Ryan E.; Cole, Banumathi K.; Hoang, Stephen A.; Lawson, Mark; Olson, Matthew W.; Figler, Robert A.; Reardon, John E.; Nishigaki, Nobuhiro; Wamhoff, Brian R.; Günther, Ulrich L.; Hirschfield, Gideon; Erion, Derek M.

doi:10.1016/j.jhepr.2020.100217

Cited by 36 publications

(33 citation statements)

References 57 publications

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“…Hence, rats may be an ideal experimental model for studying fructose metabolism and KHK inhibition. Supporting this concept, a manuscript was accepted for publication during the submission of this study demonstrating that PF-06835919 prevented triglyceride accumulation and fibrotic gene expression in human hepatocyte co-cultures and LX-2 cells [ 29 ]. The authors also demonstrated that hepatocytes are capable of synthesizing endogenous fructose from glucose via the polyol pathway and that inhibition of the metabolism of this endogenous fructose reduces glucose-induced triglyceride accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…KHK is essential for fructose metabolism as humans with loss-of-function KHK mutations and KHK-null mice fail to metabolize fructose, leading to the accumulation of fructose in plasma and urinary excretion [ [24] , [25] , [26] ]. Additionally, genetic deletion of KHK or knockdown with small interfering RNA protects mice from the deleterious metabolic effects of fructose, including obesity, insulin resistance, steatosis, hyperlipidemia, and hepatic inflammation, supporting therapeutic targeting of KHK as a method of mitigating metabolic diseases including NAFLD/NASH, T2D, and cardiovascular disease [ [26] , [27] , [28] , [29] ].…”

Section: Introductionmentioning

confidence: 99%

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Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction

Gutierrez

Liu

Perez

et al. 2021

Molecular Metabolism

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Objective Recent studies suggest that excess dietary fructose contributes to metabolic dysfunction by promoting insulin resistance, de novo lipogenesis (DNL), and hepatic steatosis, thereby increasing the risk of obesity, type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH), and related comorbidities. Whether this metabolic dysfunction is driven by the excess dietary calories contained in fructose or whether fructose catabolism itself is uniquely pathogenic remains controversial. We sought to test whether a small molecule inhibitor of the primary fructose metabolizing enzyme ketohexokinase (KHK) can ameliorate the metabolic effects of fructose. Methods The KHK inhibitor PF-06835919 was used to block fructose metabolism in primary hepatocytes and Sprague Dawley rats fed either a high-fructose diet (30% fructose kcal/g) or a diet reflecting the average macronutrient dietary content of an American diet (AD) (7.5% fructose kcal/g). The effects of fructose consumption and KHK inhibition on hepatic steatosis, insulin resistance, and hyperlipidemia were evaluated, along with the activation of DNL and the enzymes that regulate lipid synthesis. A metabolomic analysis was performed to confirm KHK inhibition and understand metabolite changes in response to fructose metabolism in vitro and in vivo. Additionally, the effects of administering a single ascending dose of PF-06835919 on fructose metabolism markers in healthy human study participants were assessed in a randomized placebo-controlled phase 1 study. Results Inhibition of KHK in rats prevented hyperinsulinemia and hypertriglyceridemia from fructose feeding. Supraphysiologic levels of dietary fructose were not necessary to cause metabolic dysfunction as rats fed the American diet developed hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis, which were all reversed by KHK inhibition. Reversal of the metabolic effects of fructose coincided with reductions in DNL and inactivation of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP). We report that administering single oral doses of PF-06835919 was safe and well tolerated in healthy study participants and dose-dependently increased plasma fructose indicative of KHK inhibition. Conclusions Fructose consumption in rats promoted features of metabolic dysfunction seen in metabolic diseases such as T2D and NASH, including insulin resistance, hypertriglyceridemia, and hepatic steatosis, which were reversed by KHK inhibition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction

Gutierrez

Liu

Perez

et al. 2021

Molecular Metabolism

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“…Fructose consumption (such as via sugared sweetened beverages) is associated with extensive metabolic dysfunction, including insulin resistance, altered gut microbiota, dysregulated lipid metabolism and hepatic steatosis (29). Fructose further bypasses several regulated steps in hexose metabolism and can directly serve as a substrate for de novo lipogenesis (30,31); this has led to efforts to use ketohexokinase inhibitors as a treatment of NASH (NCT03248882) (32,33).…”

Section: Diet and The Extrahepatic Milieumentioning

confidence: 99%

Gene-Environmental Interactions as Metabolic Drivers of Nonalcoholic Steatohepatitis

Albhaisi

Sanyal

2021

Front. Endocrinol.

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Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide in the past few decades as a consequence of the global obesity epidemic and is associated with significant morbidity and mortality. NAFLD is closely associated with components of the metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease, suggesting a plausible metabolic mechanistic basis. Metabolic inflexibility is considered a nidus for NAFLD pathogenesis, causing lipotoxicity, mitochondrial dysfunction and cellular stress leading to inflammation, apoptosis and fibrogenesis, thus mediating disease progression into nonalcoholic steatohepatitis (NASH) and ultimately cirrhosis. In this review, we describe they key metabolic drivers that contribute to development of NAFLD and NASH, and we explain how NASH is a metabolic disease. Understanding the metabolic basis of NASH is crucial for the prevention and treatment of this disease.

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“…There is increased hepatic fatty acid synthesis and de novo lipogenesis, which is, in part, due to increased fatty acid influx to the liver from lipolysis in adipose tissue. Insulin resistance accompanies the hepatic steatosis, and this, combined with exposure to a high carbohydrate diet [7,8], particularly one rich in fructose [9], further amplifies hepatic de novo lipogenesis. Steatosis by itself may be relatively benign [6] but sensitizes hepatic cells to subsequent damaging insult [10] in the form of reactive oxygen species or other proinflammatory signal.…”

Section: The Pathogenesis Of Nafldmentioning

confidence: 99%

The Impact of the NLRP3 Pathway in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease

Sheriff

2021

Livers

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The presence of hepatic steatosis and inflammation is increasingly associated with both metabolic and alcohol-related liver conditions. Both are on the increase globally and, apart from liver transplantation, there are no licensed therapies that target the full complement of disease features. The presence of some shared pathogenic mechanisms and histological features in NAFLD and ALD suggests that it may be possible to develop markers for prognostication or staging, or indeed new therapeutic tools to treat both conditions. One such example of an approach exists in the form of the NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. Activation of the NLRP3 inflammasome results in hepatocyte pyroptosis, persistence, and amplification of liver inflammation and activation of profibrogenic signaling cascades. Thus, targeting elements of the pathway in NAFLD and ALD may provide a tractable route to pharmacological therapy. In this review, we summarize the contribution of this inflammasome to disease and review the current options for therapy.

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Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis

Cited by 36 publications

References 57 publications

Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction

Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction

Gene-Environmental Interactions as Metabolic Drivers of Nonalcoholic Steatohepatitis

The Impact of the NLRP3 Pathway in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease

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