Hepatic GH Resistance Increases De Novo Lipogenesis Independent of Sex, but Only Leads to Fatty Liver in Males

Presentation Number: OR28-1
Date of Presentation: March 7th, 2015

Jose Cordoba-Chacon*1, Neena Majumdar2, Michelle Puchowicz3, Stuart J Frank4, Edward O List5, John J Kopchick5 and Rhonda D. Kineman1
1& Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, 2Jesse Brown VA Medical Center/University of Illinois at Chicago, Chicago, IL, 3Case Western Reserve University, Cleveland, 4University of Alabama at Birmingham, Birmingham, AL, 5Ohio University, Athens, OH


Enhanced de novo lipogenesis (DNL) is thought to contribute to non-alcoholic fatty liver disease (NAFLD). Progression of NAFLD is also associated with low IGF-I suggesting hepatic GH resistance. Developmental, liver-specific GH resistance, in mice, promotes hepatic lipid accumulation.  This is due in part to low IGF-I and high GH levels that favor insulin resistance and white adipose tissue (WAT) lipolysis, leading to hepatic fatty acid reesterification. By contrast, GH overexpression in diet-induced obese rats, or GH replacement in GH-deficient patients, resolves fatty liver. This positive action of GH could be due to direct antagonism of insulin-mediated hepatic lipogenesis and triglyceride (TG) storage or to indirect mechanisms (ex: IGF-I dependent promotion of peripheral insulin sensitivity). To determine whether GH directly regulates hepatic lipid metabolism in adults, hepatic GH receptor (GHR) expression was knocked-down in 10wk-old GHR floxed mice by iv injection of an adeno-associated virus bearing a hepatocyte-specific promoter driven Cre recombinase. This resulted in adult-onset hepatocyte-specific knockdown of the GHR (aLivGHRkd). Just 7 days after aLivGHRkd, the rate of hepatic DNL, measured by heavy-water labeling, was more than doubled, in both male and female mice fed a standard chow diet. As previously reported, hepatic TG content doubled in male, but not female, aLivGHRkd mice, likely due to an estrogen-dependent mechanism. In male aLivGHRkd mice, the increase in DNL and hepatic TG content could not be attributed to changes in hepatic proximal insulin signaling, fatty acid mobilization due to WAT lipolysis, secretion rate of hepatic VLDL, or clearance of postprandial lipoproteins/chylomicrons. In addition, no consistent changes were observed in the expression of lipogenic genes (ACC1, FASN and ELOV6) or maturation of SREBP1c. These results suggest that aLivGHRkd does not alter the classic pathway used by insulin to promote hepatic TG synthesis/accumulation. Interestingly, PPARγ and glucokinase (Gck, a PPARγ target gene) mRNA and protein levels were consistently increased in aLivGHRkd livers. In fact, cytosolic/active Gck was increased which suggests an enhanced glycolytic flux to provide energy and substrates to sustain an enhanced rate of DNL.  The increase in DNL was associated with a decrease in fatty acid oxidation (β-hydroxybutyryl-CoA levels were low), while acetyl-CoA levels were maintained and malonyl-CoA levels tended to be increased as supported by a reduction in the P-ACC/ACC ratio. Taken together, these data demonstrate GH normally suppresses hepatic DNL, in part by controlling substrate availability by regulating Gck/glycolytic flux. These novel findings raise the possibility that hepatic GH resistance or reduced hepatic GH input could contribute to the progression of NAFLD by maintaining inappropriate DNL.


Disclosure: JC: Recipient Award, Genentech, Inc.. RDK: Jose Cordoba-Chacon, PhD was intergral in performing and interpretin many of the studies to be discussed. He has recieved a post-doctoral research award (Endocrine Scholar Award for GH Research 2014) from Genetech, Genentech, Inc.. Nothing to Disclose: NM, MP, SJF, EOL, JJK