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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/E1115    most recent 91031.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Suzuki, J. Articles by Miyamori, I. PubMed PubMed Citation Articles by Suzuki, J. Articles by Miyamori, I.

Effects of hormone-sensitive lipase disruption on cardiac energy metabolism in response to fasting and refeeding

¹Third Department of Internal Medicine and ²The Research and Education Program for Life Science, University of Fukui, Faculty of Medical Science, Fukui; ³Division of Endocrinology and Metabolism, Department of Medicine, and ⁴Division of Bioimaging Sciences, Center for Molecular Medicine, Jichi Medical University, Tochigi; ⁵Department of Molecular Pharmacology, Shinshu University, School of Medicine, Matsumoto, Japan; and ⁶Veterans Affairs Palo Alto Health Care System, Palo Alto, and Division of Endocrinology, Stanford University, Stanford, California

Submitted 28 December 2008 ; accepted in final form 18 August 2009

Increased fatty acid (FA) flux and intracellular lipid accumulation (steatosis) give rise to cardiac lipotoxicity in both pathological and physiological conditions. Since hormone-sensitive lipase (HSL) contributes to intracellular lipolysis in adipose tissue and heart, we investigated the impact of HSL disruption on cardiac energy metabolism in response to fasting and refeeding. HSL-knockout (KO) mice and wild-type (WT) littermates were fasted for 24 h, followed by 6 h of refeeding. Plasma FA concentration in WT mice was elevated twofold with fasting, whereas KO mice lacked this elevation, resulting in twofold lower cardiac FA uptake compared with WT mice. Echocardiography showed that fractional shortening was 15% decreased during fasting in WT mice and was associated with steatosis, whereas both of these changes were absent in KO mice. Compared with Langendorff-perfused hearts isolated from fasted WT mice, the isolated KO hearts also displayed higher contractile function and a blunted response to FA. Although cardiac glucose uptake in KO mice was comparable with WT mice under all conditions tested, cardiac VLDL uptake and lipoprotein lipase (LPL) activity were twofold higher in KO mice during fasting. The KO hearts showed undetectable activity of neutral cholesteryl esterase and 40% lower non-LPL triglyceride lipase activity compared with WT hearts in refed conditions accompanied by overt steatosis, normal cardiac function, and increased mRNA expression of adipose differentiation-related protein. Thus, the dissociation between cardiac steatosis and functional sequelae observed in HSL-KO mice suggests that excess FA influx, rather than steatosis per se, appears to play an important role in the pathogenesis of cardiac lipotoxicity.

lipolysis; cardiac steatosis; lipotoxicity