Regulation of retinol‐binding protein 4 and retinol metabolism in fatty liver disease

Vitamin A refers to a spectrum of retinoid compounds (retinol, retinoic acid, and retinaldehyde) with important functions in different tissues, including the retina and skin. Retinoids regulate metabolic pathways through binding to two nuclear hormone receptors: retinoic acid receptor and retinoid X receptor. In humans, approximately 80% of the body reservoir of vitamin A is stored in the liver as retinyl ester in hepatic stellate cells (HSCs). Upon physiological cues, retinoids are released in a controlled fashion and bind to retinol-binding protein 4 (RBP4) in the circulation. Retinoids are also released by activated HSCs during liver damage; activation of these cells plays a key role in progression of liver damage and fibrogenesis, but the consequence of the retinoid release under these circumstances is poorly understood. Changes in RBP4 levels seem to play a role in nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome (MetS) and, now, the leading cause of liver damage. Indeed, epidemiological studies have shown that higher RBP4 levels are associated with MetS and NAFLD. Moreover, changes in RBP4 levels may contribute to insulin resistance (IR) and liver steatosis (LS) by influencing hepatic de novo lipogenesis. However, the mechanisms linking increased RBP4 with NAFLD are unknown. In this issue, Lee et al. describe a new transgenic mouse model overexpressing human RBP4 specifically in the adipose tissue (adi-hRBP4 mice). The highlight of this study is to test in vivo the hypothesis that ectopic human RBP4 overexpression in the adipose tissue can influence hepatic steatosis (HS). When fed a high-fat diet, adi-hRBP4 mice showed higher susceptibility to HS as a result of adipose tissue inflammation, IR, and increased free fatty acid (FFA) flux to the liver. These mice also had reduced glucose tolerance and thus exhibited the features of MetS associated with NAFLD. This phenotype did not appear to be dependent on overt alterations of retinoid metabolism. The importance of this work resides in showing how intracellular overexpression of RBP4 in adipose tissue results in a redistribution of fat from the adipose to the liver by activating lipases and promoting inflammation. The investigators propose that liver disease starts when RBP4 levels increase in the adipose tissue and that increased circulating RBP4 levels are a consequence, and not a cause, of disease. This model would be consistent with the fact that a specific RBP4-dependent intracellular signaling pathway mediating the effects of circulating RBP4 has not been identified. However, a limitation of this work is that body weight was higher in the adi-hRBP4, compared to the Abbreviations: FFA, free fatty acid; HS, hepatic steatosis; HSCs, hepatic stellate cells; IR, insulin resistance; LS, liver steatosis; MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; PNPLA3, patatin-like phospholipase domain-containing 3; RBP4, retinol-binding protein 4.