Journal article

Inhibition of Adenosine Monophosphate-Activated Protein Kinase-3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Signaling Leads to Hypercholesterolemia and Promotes Hepatic Steatosis and Insulin Resistance

Kim Loh, Shanna Tam, Lisa Murray-Segal, Kevin Huynh, Peter J Meikle, John W Scott, Bryce van Denderen, Zhiping Chen, Rohan Steel, Nicholas D LeBlond, Leah A Burkovsky, Conor O'Dwyer, Julia RC Nunes, Gregory R Steinberg, Morgan D Fullerton, Sandra Galic, Bruce E Kemp

HEPATOLOGY COMMUNICATIONS | JOHN WILEY & SONS LTD | Published : 2019

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) regulates multiple signaling pathways involved in glucose and lipid metabolism in response to changes in hormonal and nutrient status. Cell culture studies have shown that AMPK phosphorylation and inhibition of the rate-limiting enzyme in the mevalonate pathway 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase (HMGCR) at serine-871 (Ser871; human HMGCR Ser872) suppresses cholesterol synthesis. In order to evaluate the role of AMPK-HMGCR signaling in vivo, we generated mice with a Ser871-alanine (Ala) knock-in mutation (HMGCR KI). Cholesterol synthesis was significantly suppressed in wild-type (WT) but not in HMGCR KI hepatocyt..

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Grants

Awarded by National Health and Medical Research Council of Australia


Awarded by Canadian Institutes of Health Research


Funding Acknowledgements

Supported by the National Health and Medical Research Council of Australia (Fellowship 1078752 to B.E.K.; project grants 1080473 to K.L. and 1085460 to B.E.K., S.G., and G.R.S.), Canadian Institutes of Health Research (project grant PJT148634 to M.D.F.; New Investigator Award to M.D.F.), Canadian Liver Foundation (operating funding to M.D.F.; summer studentship award to L.A.B.), Canada Research Chair in Metabolism and Obesity and J. Bruce Duncan Chair in Metabolic Diseases (to G.R.S.), Victorian Government's Operational Infrastructure Support Program, and the L.E.W Carty Charitable Fund (to K.L.).