Retinoic acid receptor α signaling protects against diet‐induced hepatosteatosis and obesity in mice

Retinoic acid receptor α signaling protects against diet‐induced hepatosteatosis and obesity in mice

Bawa F;Xu Y;Zhu Y;Chen S;Gopoju R;Zhang Y

Faseb Journal

2020

2020-04

Nonalcoholic fatty liver disease (NAFLD) is often characterized by accumulation of lipids in the liver. It presents a pathological spectrum of changes from simple steatosis to steatohepatitis. It is also often associated with obesity and insulin resistance. Since liver is the main organ involved in retinoid signaling, the impairment of this pathway is shown to increase liver fibrosis with the activation of stellate cells which stores retinoids in liver. However, the role of the retinoid signaling in NAFLD and obesity is not fully understood. Some studies have shown that retinoic acid treatment can ameliorate insulin resistance and obesity. We hypothesize that Retinoic Acid Receptor α (RARα) in hepatocytes play a significant role in mediating retinoid signaling to protect against NAFLD and obesity. To address this hypothesis, we conducted in vivo studies using liver‐specific Rarα knockout mice. Rarα floxed mice were injected with AAV8‐TBG‐Cre or AAV8‐TBG‐Null to generate liver‐specific Rarα knockout mice (L‐Rarα−/−) mice and the control mice (Rarαfl/fl). These mice were gavaged with either vehicle or all‐trans retinoic acid (AtRA; 15mg/kg/day) along with high fat/high cholesterol/high fructose (HFCF) diet for 16 weeks. The data showed that AtRA treatment reduced body fat content and increased energy expenditure in the control mice but not in L‐Rarα−/− mice. In addition, AtRA reduced hepatic triglyceride (TG) levels in both the control mice and L‐Rarα−/− mice with a greater extent in reduction of hepatic TG levels in the control mice. Analysis of hepatic gene expression by qRT‐PCR showed that AtRA reduced hepatic levels of genes involved in lipogenesis and fatty acid uptake (Pparγ, Cd36 and L‐Fabp) or inflammation (Tnf‐α) in the control mice, but not in L‐RARα−/− mice. Similar observations were collected in a different study where control mice and L‐Rara−/− mice were fed an HFCF diet for 20 weeks, followed by 10 weeks of treatment with either vehicle or AtRA. Our data demonstrate that the retinoid signaling protects against the development of hepatosteatosis and obesity in a Rarα‐dependent manner.

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