title: Stearoyl-CoA desaturase 1 deficiency reduces lipid accumulation in the heart by activating lipolysis independently of peroxisome proliferator-activated receptor α.
abstract: Stearoyl-CoA desaturase 1 (SCD1) has recently been shown to be a critical control point in the regulation of cardiac metabolism and function. Peroxisome proliferator-activated receptor α (PPARα) is an important regulator of myocardial fatty acid uptake and utilization. The present study used SCD1 and PPARα double knockout (SCD1-/-/PPARα-/-) mice to test the hypothesis that PPARα is involved in metabolic changes in the heart that are caused by SCD1 downregulation/inhibition. SCD1 deficiency decreased the intracellular content of free fatty acids, triglycerides, and ceramide in the heart of SCD1-/-and SCD1-/-/PPARα-/-mice. SCD1 ablation in PPARα-/-mice decreased diacylglycerol content in cardiomyocytes. These results indicate that the reduction of fat accumulation in the heart associated with SCD1 deficiency occurs independently of the PPARα pathway. To elucidate the mechanism of the observed changes, we treated HL-1 cardiomyocytes with the SCD1 inhibitor A939572 and/or PPARα inhibitor GW6471. SCD1 inhibition decreased the level of lipogenic proteins and increased lipolysis, reflected by a decrease in the content of adipose triglyceride lipase inhibitor G0S2 and a decrease in the ratio of phosphorylated hormone-sensitive lipase (HSL) at Ser565 to HSL (pHSL[Ser565]/HSL). PPARα inhibition alone did not affect the aforementioned protein levels. Finally, PPARα inhibition decreased the phosphorylation level of 5'-adenosine monophosphate-activated protein kinase, indicating lower mitochondrial fatty acid oxidation. In summary, SCD1 ablation/inhibition decreased cardiac lipid content independently of the action of PPARα by reducing lipogenesis and activating lipolysis. The present data suggest that SCD1 is an important component in maintaining proper cardiac lipid metabolism.
authors.affiliation: Laboratory of Molecular Medical Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bednarski
authors.affiliation: Laboratory of Molecular Medical Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Olichwier
authors.affiliation: Laboratory of Molecular Medical Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Opasinska
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pyrkowska
authors.affiliation: Laboratory of Molecular Medical Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Gan
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA; Department Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Ntambi
authors.affiliation: Laboratory of Molecular Medical Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. Electronic address: p.dobrzyn@nencki.gov.pl.
authors.forename: Pawel
authors.initials: P
authors.lastname: Dobrzyn
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology*; D008055:Lipids / Q000502:physiology*; D050155:Lipogenesis / Q000502:physiology; D008066:Lipolysis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D013230:Stearoyl-CoA Desaturase / Q000172:deficiency*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D002518:Ceramides; D005230:Fatty Acids, Nonesterified; D008055:Lipids; D047495:PPAR gamma; D014280:Triglycerides; D000249:Adenosine Monophosphate; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase
keywords: ATGL; Cardiomyocytes; Lipogenesis; Lipolysis; PPARα; Triglyceride