Growth Hormone Control of Hepatic Lipid Metabolism

Abstract

In humans, low levels of growth hormone (GH) and its mediator, IGF-1, associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin resistance. Due to the intricate relationship between GH and IGF-1, the relative contribution of each hormone to the development of hepatic steatosis is unclear. Our goal was to dissect the mechanisms by which hepatic GH resistance leads to steatosis and overall insulin resistance, independent of IGF-1. We have generated a combined mouse model with liver-specific ablation of GHR in which we restored liver IGF-1 expression via the hepatic IGF-1 transgene. We found that liver GHR ablation leads to increases in lipid uptake, de novo lipogenesis, hyperinsulinemia, and hyperglycemia accompanied with severe insulin resistance and increased body adiposity and serum lipids. Restoration of IGF-1 improved overall insulin sensitivity and lipid profile in serum and reduced body adiposity, but was insufficient to protect against steatosis-induced hepatic inflammation or oxidative stress. We conclude that the impaired metabolism in states of GH resistance results from direct actions of GH on lipid uptake and de novo lipogenesis, whereas its actions on extrahepatic tissues are mediated by IGF-1.

Reduced Serum IGF-1 Associated With Hepatic Osteodystrophy Is a Main Determinant of Low Cortical but Not Trabecular Bone Mass

“…NAFLD in the Li‐GHRKO and Li‐GHRKO‐HIT occurs as early as 6 weeks of age, during puberty, when trabecular bone acquisition peaks and cortical bone continues to mineralize. In addition to hepatic inflammation, we found increases in the expression of oxidative stress markers in livers of Li‐GHRKO and the Li‐GHRKO‐HIT mice . Previous studies have linked oxidative stress with impaired bone remodeling and low bone mass .…”

“…We recently created a combined mouse model with liver GHR deletion (Li-GHRKO), in which we restored IGF-1 production via hepatic IGF-1 transgene (HIT), the Li-GHRKO-HIT mouse. (28) In that study, we show that normalized serum IGF-1 levels in the Li-GHRKO-HIT mice improved systemic dyslipidemia and insulin resistance but did not resolve NAFLD or hepatic inflammation. NAFLD in the Li-GHRKO and Li-GHRKO-HIT occurs as early as 6 weeks of age, during puberty, when trabecular bone acquisition peaks and cortical bone continues to mineralize.…”

“…In line with this evidence, the superoxide dismutase‐1 (SOD1) null mice exhibit reductions in BMD in both male and female mice compared with control littermates, suggesting important roles for ROS inactivation in bone cells by SOD1. In our initial characterization of the Li‐GHRKO and the Li‐GHRKO‐HIT mouse models, we found increased oxidative stress markers in liver and serum of the Li‐GHRKO that were partially resolved in the young (16‐ to 52‐week‐old) Li‐GHRKO‐HIT mice . Here we tested whether oxidative stress imposed on the Li‐GHRKO and the Li‐GHRKO‐HIT relates to their bone phenotype.…”

“…We recently created a combined mouse model with liver GHR deletion (Li‐GHRKO), in which we restored IGF‐1 production via hepatic IGF‐1 transgene (HIT), the Li‐GHRKO‐HIT mouse . In that study, we show that normalized serum IGF‐1 levels in the Li‐GHRKO‐HIT mice improved systemic dyslipidemia and insulin resistance but did not resolve NAFLD or hepatic inflammation.…”

Association study between growth hormone receptor (GHR) gene polymorphisms and obesity in Korean population

“…And GH action is related to body energy expenditure and body weight (Glad et al, 2015; Haruta et al, 2015; Liu et al, 2016). It is a major hormone in insulin resistance and body weight control.…”