Retinol-Binding Protein 4 Induces Hepatic Mitochondrial Dysfunction and Promotes Hepatic Steatosis

Context and Objective: Elevated serum retinol-binding protein 4 (RBP4) has been implicated in insulin resistant and nonalcoholic fatty liver disease (NAFLD) subjects; however, the molecular mechanism of RBP4 in NAFLD remains obscure. Design and Participants: Hepatic RBP4 mRNA level and its association with lipid accumulation were examined in NAFLD patients and mouse model. Furthermore, human RBP4 overexpressing (RBP4-Tg) mice were metabolically phenotyped after either a regular chow or high-fat diet. Results: RBP4 mRNA was aberrantly elevated in NAFLD models and positively associated with increased hepatic triglyceride accumulation. Compared with their wild-type littermates, RBP4-Tg mice fed regular chow had increased hepatic lipid accumulation associated with cellular ballooning and inflammatory changes, which was exacerbated when challenged with high-fat diet. The acceleration of NAFLD in RBP4-Tg mice was mainly attributed to reduced mitochondrial content and impaired mitochondria' fatty acid beta-oxidation. RBP4 overexpression promoted the acetylation of long-chain acyl-coenzyme A dehydrogenase through inhibiting the expression and activity of NAD-dependent deacetylase sirtuin-3 and significantly hampered the binding of long-chain acylcoenzyme A dehydrogenase and NAD-dependent deacetylase sirtuin-3. Moreover, RBP4-induced mitochondria' dysfunction preceded the deterioration of lipid metabolism. Conclusions: These results have unraveled a novel role of RBP4 in hepatic mitochondrial dysfunction and steatosis and suggest that RBP4 might be a potential target for the early prevention of NAFLD.