Hepatic deficiency of selenoprotein S exacerbates hepatic steatosis and insulin resistance

<jats:title>Abstract</jats:title><jats:p>Nonalcoholic fatty liver disease (NAFLD) is closely associated with insulin resistance (IR) and type 2 diabetes mellitus (T2DM), which are all complex metabolic disorders. Selenoprotein S (SelS) is an endoplasmic reticulum (ER) resident selenoprotein involved in regulating ER stress and has been found to participate in the occurrence and development of IR and T2DM. However, the potential role and mechanism of SelS in NAFLD remains unclear. Here, we analyzed SelS expression in the liver of high-fat diet (HFD)-fed mice and obese T2DM model (<jats:italic>db/db</jats:italic>) mice and generated hepatocyte-specific SelS knockout (<jats:italic>SelS</jats:italic><jats:sup><jats:italic>H-KO</jats:italic></jats:sup>) mice using the Cre-loxP system. We showed that hepatic SelS expression levels were significantly downregulated in HFD-fed mice and <jats:italic>db/db</jats:italic> mice. Hepatic SelS deficiency markedly increased ER stress markers in the liver and caused hepatic steatosis via increased fatty acid uptake and reduced fatty acid oxidation. Impaired insulin signaling was detected in the liver of <jats:italic>SelS</jats:italic><jats:sup><jats:italic>H-KO</jats:italic></jats:sup> mice with decreased phosphorylation levels of insulin receptor substrate 1 (IRS1) and protein kinase B (PKB/Akt), which ultimately led to disturbed glucose homeostasis. Meanwhile, our results showed hepatic protein kinase Cɛ (PKCɛ) activation participated in the negative regulation of insulin signaling in <jats:italic>SelS</jats:italic><jats:sup><jats:italic>H-KO</jats:italic></jats:sup> mice. Moreover, the inhibitory effect of SelS on hepatic steatosis and IR was confirmed by SelS overexpression in primary hepatocytes in vitro. Thus, we conclude that hepatic SelS plays a key role in regulating hepatic lipid accumulation and insulin action, suggesting that SelS may be a potential intervention target for the prevention and treatment of NAFLD and T2DM.</jats:p>