Emerging molecular targets for the treatment of nonalcoholic fatty liver disease.
ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, viral infection, or other specific causes of liver disease. Currently the most common chronic liver disease, affecting 30% of the Western world, NAFLD may progress to cirrhosis and end-stage liver disease and may increase the risk of developing diabetes and cardiovascular disease. Although its pathogenesis is unclear, NAFLD is tightly associated with insulin resistance and the metabolic syndrome. No established treatment exists, and current research is targeting new molecular mechanisms that underlie NAFLD and associated cardiometabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications for the treatment of NAFLD: microRNAs, incretin analogs/antagonists, liver-specific thyromimetics, AMP-activated protein kinase activators, and nuclear receptors farnesoid X receptor and pregane X receptor.
- SourceAvailable from: onlinelibrary.wiley.comJournal of Gastroenterology and Hepatology 08/2013; 28(S1). · 3.33 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The present study was to investigate whether high molecular weight persimmon tannin (HMWPT) is the main component associated with the anti-hyperlipidemic effect of consuming persimmon and its underlying mechanism. Male wistar rats were given a basic diet (control), a high-fat diet, a high-fat diet plus 0.5% of HMWPT or 4.2% of lyophilized fresh persimmon fruit (with the same diet HMWPT content in the two groups) for 9 weeks. Administration of HMWPT or persimmon fruit significantly (p < 0.05) lowered serum triglycerides and free fatty acids, enhanced the excretion of triglycerides, cholesterol and bile acids, and improved hepatic steatosis in rats fed a high-fat diet. Dietary HMWPT or persimmon fruit significantly decreased the protein levels of fatty acid synthase (FAS), and stimulated AMP-activated protein kinase (AMPK) phosphorylation and down-regulated genes involved in lipogenesis, including transcriptional factor sterol regulatory element binding protein 1 (SREBP1) and acetyl CoA carboxylase (ACC). In addition, the expression of proteins involved in fatty acid oxidation, such as carnitine palmitoyltransferase-1 (CPT-1), was notably up-regulated. Furthermore, HMWPT and persimmon fruit suppressed inflammatory cytokines such as tumor necrosis factor α (TNFα) and C-reactive protein (CRP) and the protein level of nuclear factor-kappa B (NFκB) in the liver. Taken together, our findings demonstrated that HMWPT reproduced the anti-hyperlipidemic effects of persimmon fruit, and was a pivotal constituent of persimmon fruit accounting for prevention of liver steatosis and its progression to nonalcoholic steatohepatitis (NASH) by activation of the AMPK and regulation of its downstream targets, suppressing NF-κB activation and inflammatory responses, and inhibiting lipids and bile acid absorption.Food & Function 05/2014; · 2.91 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The protein, thyroid hormone‐responsive SPOT 14 homolog (Thrsp), has been reported to be a lipogenic gene in cultured hepatocytes, implicating an important role of Thrsp in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Thrsp expression is known to be regulated by a variety of transcription factors, including thyroid hormone receptor, pregnane X receptor, and constitutive androstane receptor. Emerging in vitro evidence also points to a critical role of liver X receptor (LXR) in regulating Thrsp transcription in hepatocytes. In the present study, we showed that Thrsp was up‐regulated in livers of db/db mice and high‐fat‐diet–fed mice, two models of murine NAFLD. Hepatic overexpression of Thrsp increased triglyceride accumulation with enhanced lipogenesis in livers of C57Bl/6 mice, whereas hepatic Thrsp gene silencing attenuated the fatty liver phenotype in db/db mice. LXR activator TO901317 induced Thrsp expression in livers of wild‐type (WT) and LXR‐β gene‐deficient mice, but not in LXR‐α or LXR‐α/β double‐knockout mice. TO901317 treatment significantly enhanced hepatic sterol regulatory element‐binding protein 1c (SREBP‐1c) expression and activity in WT mice, but failed to induce Thrsp expression in SREBP‐1c gene‐deficient mice. Sequence analysis revealed four LXR response‐element–like elements and one sterol regulatory element (SRE)‐binding site within a −2,468 ∼+1‐base‐pair region of the Thrsp promoter. TO901317 treatment and LXR‐α overexpression failed to induce, whereas overexpression of SREBP‐1c significantly increased Thrsp promoter activity. Moreover, deletion of the SRE site completely abolished SREBP‐1c–induced Thrsp transcription. Conclusion: Thrsp is a lipogenic gene in the liver that is induced by the LXR agonist through an LXR‐α–mediated, SREBP‐1c–dependent mechanism. Therefore, Thrsp may represent a potential therapeutic target for the treatment of NAFLD. (Hepatology 2013;58:617–628)Hepatology 01/2013; 58(2). · 11.19 Impact Factor