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[Online ahead of print]

Vitamin D Receptor Targets Hepatocyte Nuclear Factor 4α and Mediates Protective Effects of Vitamin D in Nonalcoholic Fatty Liver Disease

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Vitamin D Receptor Targets Hepatocyte Nuclear Factor 4α and Mediates Protective Effects of Vitamin D in Nonalcoholic Fatty Liver Disease

Hong Zhang et al. J Biol Chem.

Abstract

Epidemiological studies have suggested a link between vitamin D deficiency and increased risk for nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms have remained unclear. Here, using both clinical samples and experimental rodent models along with several biochemical approaches, we explored the specific effects and mechanisms of vitamin D deficiency in NAFLD pathology. Serum vitamin D levels were significantly lower in individuals with NAFLD and in high-fat diet (HFD)-fed mice than in healthy controls and chow-fed mice, respectively. Vitamin D supplementation ameliorated HFD-induced hepatic steatosis and insulin resistance in mice. Hepatic expression of vitamin D receptor (VDR) was up-regulated in three models of NAFLD, including HFD-fed mice, methionine/choline-deficient diet (MCD)-fed mice, and genetically obese (ob/ob) mice. Liver-specific VDR deletion significantly exacerbated HFD- or MCD-induced hepatic steatosis and insulin resistance and also diminished the protective effect of vitamin D supplementation on NAFLD. Mechanistic experiments revealed that VDR interacted with hepatocyte nuclear factor 4 α (HNF4α) and that overexpression of HNF4α improved HFD-induced NAFLD and metabolic abnormalities in liver-specific VDR-knockout mice. These results suggest that vitamin D ameliorates NAFLD and metabolic abnormalities by activating hepatic VDR, leading to its interaction with HNF4α. Our findings highlight a potential value of using vitamin D for preventing and managing NAFLD by targeting VDR.

Keywords: gene regulation; hepatic steatosis; hepatocyte nuclear factor 4 α (HNF4α); insulin resistance; lipid metabolism; liver metabolism; metabolic syndrome; nonalcoholic fatty liver disease (NAFLD); nuclear receptor; vitamin D.

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