Hepatocyte Growth Hormone (GH) Signaling Protects the Adult Liver from Injury through Direct and Indirect Mechanisms

Presentation Number: OR18-4
Date of Presentation: April 2nd, 2017

Jose Cordoba-Chacon1, Syeda Khalid1, Natalia Nieto2, Grace Guzman2 and Rhonda D. Kineman*1
1& Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, 2University of Illinois at Chicago, Chicago, IL


Chronic liver disease (CLD) can be caused by non-alcoholic fatty liver disease (NAFLD), viral hepatitis, alcohol/drug-abuse and cholestatic diseases. Clinical and experimental studies indicate alterations in GH production and defects in hepatic GH-signaling are common features of CLD. These changes likely contribute to CLD progression since increasing GH can reverse liver injury. However, identification of the exact mechanisms by which GH mediates this positive action (direct or indirect via regulation of IGF-I) is limited by the use of congenital knockout models of hepatic GH signaling or IGF-I production, where developmental/compensatory changes impair the ability to assign a cause to the consequences observed in the adult. Therefore, we have taken a novel approach to manipulate GH signaling and IGF-I production in the ADULT mouse hepatocyte, to segregate the direct, from indirect, mechanisms of GH-modulated liver injury and repair. Specifically, mice with adult-onset, hepatocyte-specific knockdown of the GH receptor (aHepGHRkd) were generated by tranducing 10wk-old GHRfl/fl mice with an AAV8-TBGp driven Cre recombinase (AAV8-TBGp-Cre). One week after AAV8-TBGp-Cre, the GHR is reduced to <1% of controls (AAV8-TBGp-Null treated GHRfl/fl), leading to a reduction in IGF-I and an elevation in GH levels. With age (>6 mo) aHepGHRkd mice, but not controls, exhibit hepatic steatosis associated with hepatocyte ballooning, inflammation/fibrosis and insulin resistance, features of non-alcoholic steatohepatitis (NASH). To determine if liver injury in aHepGHRkd mice can occur independent of chronic steatosis and changes in systemic metabolism, liver damage was induced by carbon tetrachloride (CCl4) just 7d after aHepGHRkd, before inflammation/fibrosis and systemic insulin resistance occurs. To determine if liver injury could be modified by the shift in plasma IGF-I/GH observed after aHepGHRkd, we generated mice with adult-onset hepatocyte-specific IGF-I knockdown (aHepIGFIkd; AAV8-TBGp-Cre treated IGF-Ifl/fl) that also reduces plasma IGF-I and raises GH levels, while the hepatocyte GHR remains intact. aHepGHRkd, but not aHepIGFIkd, sensitized the liver to acute CCl4-induced liver damage (greater plasma ALT levels and centrilobular damage), without altering the ability of the hepatocyte to regenerate (% positive PCNA). After chronic CCl4 treatment, ALT levels remained elevated in aHepGHRkd mice, but were reduced in aHepIGFIkd mice. Unexpectedly, in both models fibrotic stage and grade of inflammation and apoptosis/necrosis was less than controls treated with CCl4. These preliminary studies demonstrate that GH directly protects the hepatocyte from acute injury. Since both aHepGHRkd and aHepIGFIkd mice exhibit low IGF-I and elevated GH, we hypothesize these endocrine changes control extra-hepatocyte processes, to reduce the extent of liver injury and speed repair.


Nothing to Disclose: JC, SK, NN, GG, RDK