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.
- Resource Type
- Academic Journal
- Authors
- Loh K; St. Vincent's Institute of Medical Research and Department of Medicine University of Melbourne Fitzroy Australia.; Tam S; St. Vincent's Institute of Medical Research and Department of Medicine University of Melbourne Fitzroy Australia.; Murray-Segal L; St. Vincent's Institute of Medical Research and Department of Medicine University of Melbourne Fitzroy Australia.; Huynh K; Baker Heart and Diabetes Institute Melbourne Australia.; Meikle PJ; Baker Heart and Diabetes Institute Melbourne Australia.; Scott JW; St. Vincent's Institute of Medical Research and Department of Medicine University of Melbourne Fitzroy Australia.; Mary MacKillop Institute for Health Research Australian Catholic University Fitzroy Australia.; The Florey Institute of Neuroscience and Mental Health Parville Australia.; van Denderen B; St. Vincent's Institute of Medical Research and Department of Medicine University of Melbourne Fitzroy Australia.; Chen Z; St. Vincent's Institute of Medical Research and Department of Medicine University of Melbourne Fitzroy Australia.; Steel R; St. Vincent's Institute of Medical Research and Department of Medicine University of Melbourne Fitzroy Australia.; LeBlond ND; Department of Biochemistry, Microbiology and Immunology University of Ottawa Ottawa Canada.; Burkovsky LA; Department of Biochemistry, Microbiology and Immunology University of Ottawa Ottawa Canada.; O'Dwyer C; Department of Biochemistry, Microbiology and Immunology University of Ottawa Ottawa Canada.; Nunes JRC; Department of Biochemistry, Microbiology and Immunology University of Ottawa Ottawa Canada.; Steinberg GR; Division of Endocrinology and Metabolism, Department of Medicine and Department of Biochemistry and Biomedical Sciences McMaster University Hamilton Canada.; Fullerton MD; Department of Biochemistry, Microbiology and Immunology University of Ottawa Ottawa Canada.; Galic S; St. Vincent's Institute of Medical Research and Department of Medicine University of Melbourne Fitzroy Australia.; Kemp BE; St. Vincent's Institute of Medical Research and Department of Medicine University of Melbourne Fitzroy Australia.; Mary MacKillop Institute for Health Research Australian Catholic University Fitzroy Australia.
- Source
- Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 101695860 Publication Model: eCollection Cited Medium: Internet ISSN: 2471-254X (Electronic) Linking ISSN: 2471254X NLM ISO Abbreviation: Hepatol Commun Subsets: PubMed not MEDLINE
- Subject
- Language
- English
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 hepatocytes in response to AMPK activators. Liver cholesterol synthesis and cholesterol levels were significantly up-regulated in HMGCR KI mice. When fed a high-carbohydrate diet, HMGCR KI mice had enhanced triglyceride synthesis and liver steatosis, resulting in impaired glucose homeostasis. Conclusion: AMPK-HMGCR signaling alone is sufficient to regulate both cholesterol and triglyceride synthesis under conditions of a high-carbohydrate diet. Our findings highlight the tight coupling between the mevalonate and fatty acid synthesis pathways as well as revealing a role of AMPK in suppressing the deleterious effects of a high-carbohydrate diet.