Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2

Abstract

Non-alcoholic fatty liver disease is associated with multiple comorbid conditions, including diabetes, obesity, infection, and malnutrition. Mice with hepatocyte-specific disruption of growth hormone (GH) signaling develop fatty liver (FL), although the precise mechanism underlying this finding remains unknown. Because GH signals through JAK2, we developed mice bearing hepatocyte-specific deletion of JAK2 (referred to herein as JAK2L mice). These mice were lean, but displayed markedly elevated levels of GH, liver triglycerides (TGs), and plasma FFAs. Because GH is known to promote lipolysis, we crossed GH-deficient little mice to JAK2L mice, and this rescued the FL phenotype. Expression of the fatty acid transporter CD36 was dramatically increased in livers of JAK2L mice, as was expression of Pparg. Since GH signaling represses PPARγ expression and Cd36 is a known transcriptional target of PPARγ, we treated JAK2L mice with the PPARγ-specific antagonist GW9662. This resulted in reduced expression of liver Cd36 and decreased liver TG content. These results provide a mechanism for the FL observed in mice with liver-specific disruption in GH signaling and suggest that the development of FL depends on both GH-dependent increases in plasma FFA and increased hepatic uptake of FFA, likely mediated by increased expression of CD36.

Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy

“…Furthermore, liver-specific deletion of JAK2 (35) or STAT5 (36,37) in mice results in steatosis, suggesting the importance of downstream signaling of GHR in the lipid metabolism of the hepatocytes. In an Figure 1 Serum aspartate aminotransferase and alanine aminotransferase, and g-GTP concentrations before and after GH replacement therapy for 6 months in adult patients with GHD.…”

DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

“…Moreover, we found that DLK1-overexpressing mice had elevated production of pituitary growth hormone due to a local defect in IGF1 feedback. Because impaired GH signaling is known to cause steatosis by affecting pathways of hepatic lipid import and synthesis (3)(4)(5), as well affecting peripheral FA oxidation (22), we propose that increased dosage of DLK1 acts primarily on the GH axis to shift the metabolic mode toward FA oxidation, with overall beneficial effects on hepatic lipid deposition.…”

“…Depletion of hepatic GH signaling is thought to cause accumulation of triglycerides in the liver in two ways. Firstly, ablation of GH signaling in the liver itself prevents suppression of the fatty acid translocase Cd36, and Pparγ, resulting in increased FA import and biosynthesis (3)(4)(5). Secondly, ablation of GHstimulated hepatic IGF1 release causes elevated circulating GH that induces expression of adipose tissue lipases, adipose tissue lipid mobilization, and lipid flux to the liver (5).…”

“…FA synthesis, clearance, and release are regulated by neuroendocrine factors including GH, whose levels vary under conditions of changing energy supply (2). Recent animal studies have underscored the important role of hepatic GH signaling in the development of NAFLD and the metabolic syndrome (3)(4)(5)(6).…”

Estrogens in the Control of Growth Hormone Actions in Liver

“…Several studies in bGHtransgenic mice, defficient GHR-JAK2-STAT-5 signaling pathway, GH-treated intact or GHdeficient rats (hypophysectomized or hypothyroid), as well as experiments in PPAR null mice, have all revealed that GH down-regulates genes involved in lipid oxidation and increases the expression of genes promoting lipogenesis in the liver (Olsson et al, 2003;Wang et al, 2007;Barclay et al, 2011;Sos et al, 2011). On the other hand, an impaired GHR-JAK2-STAT-5 signaling strongly correlates with hepatic steatosis (Fan et al, 2009;Barclay et al, 2011;Sos et al, 2011). Disruption of the hepatic GHR, JAK2 or STAT5 genes in mice resulted in hepatic steatosis due to enhanced lipogenesis and reduced triglyceride secretion.…”