title: Effects of hormone-sensitive lipase disruption on cardiac energy metabolism in response to fasting and refeeding.
abstract: 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.
authors.affiliation: Third Dept. of Internal Medicine, Univ. of Fukui, Faculty of Medical Science, Fukui 910-1193, Japan. jinya@u-fukui.ac.jp
authors.forename: Jinya
authors.initials: J
authors.lastname: Suzuki
authors.forename: Masami
authors.initials: M
authors.lastname: Ueno
authors.forename: Miyuki
authors.initials: M
authors.lastname: Uno
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hirose
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Zenimaru
authors.forename: Sadao
authors.initials: S
authors.lastname: Takahashi
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Osuga
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirose
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
authors.forename: Fredric B
authors.initials: FB
authors.lastname: Kraemer
authors.forename: Isamu
authors.initials: I
authors.lastname: Miyamori
mesh_terms: D000818:Animals; D004435:Eating / Q000502:physiology*; D004452:Echocardiography; D004734:Energy Metabolism / Q000187:drug effects*; D005215:Fasting / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006334:Heart Function Tests; D066298:In Vitro Techniques; D050356:Lipid Metabolism / Q000235:genetics; D008066:Lipolysis / Q000235:genetics / Q000502:physiology; D008079:Lipoproteins, VLDL / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D002787:Sterol Esterase / Q000235:genetics* / Q000502:physiology*
chemical_list: D005227:Fatty Acids; D008079:Lipoproteins, VLDL; D006003:Glycogen; D002787:Sterol Esterase; D005947:Glucose