Session: FP05-Lipids: Regulation & Mechanism of Disease
Room 133 (Moscone Center)
Poster Board SAT-728
Yong Fan, Xing Fang, Asako Tajima, Massimo Trucco, Mark A Sperling.
Department of Pediatrics, Children’s Hospital, University of Pittsburgh
Introduction:Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disorders closely related to obesity and insulin resistance. Non-alcoholic steatohepatitis (NASH) develops from NAFLD, and is characterized by lipid accumulation with evidence of hepatocellular damage, inflammation and progressive fibrosis, ultimately resulting in cirrhosis and adeno-carcinoma formation. We and others have shown that liver-specific deletion of GHR or JAK2/STAT5 signaling in mice leads to NAFLD (1-3). We investigated the progression of NAFLD over the lifespan in mice with GHRLD.
Methods: We performed sequential histology and histochemical analysis of liver samples from mice with GHRLD at 44 to 72 weeks of age on normal chow, followed by quantitative PCR for markers of inflammation (TNFalpha, CCL3, IL1a, IL1b), fibrosis (Col1A2, Col3A1, MMP13, TGFb), and liver regeneration (Egr-1). Results are reported from at least 5 mice in each group at 40-72 weeks comparing GHRLD to controls.
Results:In GHRLD, distinct nodular structure was first histologically observed at ~ 40 weeks. Microscopy (H&E) revealed the presence of areas with diminished steatosis, replaced by fibrosis and adenoma formation. Trichrome-Masson staining revealed marked increase of collagen deposition throughout the GHRLD sections. An increased mitotic index was apparent in the adenomas, in conjunction with increased markers of apoptosis. Real-time PCR analysis of key markers of inflammation revealed a 3-5 fold increase in TNFa, IL1a, IL1b, CCL3 and MMP13, confirming the severity of inflammation. The expression of fibrotic markers, Col1A2 and Col3A1, were 15-20 fold increased, together with a 70% increase in TGFb transcripts. The marker of liver regeneration, Egr-1, was 25-35 fold increased in the GHRLD liver.
Conclusion: Abrogation of GHR signaling in the liver results in hepatic steatosis due to increased synthesis and decreased export of triglyceride, which can be rescued by adenovirus-mediated GHR, but not by IGFI (1). In time, hepatic steatosis progresses to NASH, with increased markers of inflammation and fibrosis, ultimately leading to adenoma formation. Since obesity, a common precursor of NAFLD, is a state of deficient GH secretion and action (4), the GHRLD model could be used to dissect the molecular mechanisms and to identify potential targets for therapy in these pathological processes.
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Nothing to Disclose: MAS, YF, XF, AT, MT
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