Direct and systemic actions of growth hormone receptor (GHR)-signaling on hepatic glycolysis, de novo lipogenesis and insulin sensitivity, associated with steatosis.

Background: Evidence is accumulating that growth hormone (GH) protects against the development of steatosis and progression of non-alcoholic fatty liver disease (NAFLD). GH may control steatosis indirectly by altering systemic insulin sensitivity and substrate delivery to the liver and/or by the direct actions of GH on hepatocyte function.

Approach: To better define the hepatocyte-specific role of GH receptor (GHR) signaling on regulating steatosis, we used a mouse model with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd).

GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner.

A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function vs indirect effects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) signaling, independent of changes in IGF1, mice with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes.