Cardiac overexpression of hormone-sensitive lipase inhibits myocardial steatosis and fibrosis in streptozotocin diabetic mice

Abstract

Intracellular lipid accumulation (steatosis) and resultant lipotoxicity are key features of diabetic cardiomyopathy. Since cardiac hormone-sensitive lipase (HSL) is activated in diabetic mice, we sought to explore a pathophysiological function of cardiac HSL in the development of diabetic cardiomyopathy. Transgenic (Tg) mice with heart-specific HSL overexpression were generated, and cardiac histology, function, lipid profile, and gene expressions were analyzed after induction of diabetes by streptozotocin. Electron microscopy showed numerous lipid droplets in wild-type (Wt) hearts after 3 wk of diabetes, whereas Tg mice showed no lipid droplet accumulation. Cardiac content of acylglycerides was increased ∼50% with diabetes in Wt mice, whereas this was blunted in Tg hearts. Cardiac lipid peroxide content was twofold lower in Tg hearts than in Wt hearts. The mRNA expressions for peroxisome proliferator-activated receptor-α, genes for triacylglycerol synthesis, and lipoprotein lipase were increased with diabetes in Wt hearts, whereas this induction was absent in Tg hearts. Expression of genes associated with lipoapoptosis was decreased, whereas antioxidant protein metallothioneins were increased in diabetic Tg hearts. Diabetic Wt hearts showed interstitial fibrosis and increased collagen content. However, Tg hearts displayed no overt fibrosis, concomitant with decreased expression of collagens, transforming growth factor-β, and matrix metalloproteinase 2. Notably, mortality during the experimental period was approximately twofold lower in diabetic Tg mice compared with Wt mice. In conclusion, since HSL overexpression inhibits cardiac steatosis and fibrosis by apparently hydrolyzing toxic lipid metabolites, cardiac HSL could be a therapeutic target for regulating diabetic cardiomyopathy.

Liver lipid content is reduced in rat given 7-day administration of angiotensin II

“…The mRNA expression of genes related to β-oxidation was downregulated (CPT-1, PPAR-a) or unchanged (ACO, UCP2) and those related to lipogenesis (SREBP-1, FAS, HMG-CoAR) was unchanged in the liver by angiotensin II infusion. These findings were in contrast to our previous findings that accumulation of TG occurred in the kidney and heart of the same animal model, 12,13 indicating that angiotensin II-induced lipid accumulation is somehow tissue-specific, which is different from the case of diabetes in which accumulation of excessive lipids can be seen in the liver 19 as well as the kidney 20 and heart, 21 and accompanied by a modulation of lipid metabolism-related genes in these tissues. 20,[22][23] We also found that oil red O-stainable lipid was increased in the liver (unpublished observations) as well as in the kidney and heart of the rat model of metabolic syndrome.…”

Impaired Phosphatidylcholine Biosynthesis Reduces Atherosclerosis and Prevents Lipotoxic Cardiac Dysfunction in ApoE −/− Mice

“…21 The latter is particularly intriguing because the cardiac TG pool can be turned over rapidly 28 and may contribute to the metabolic fate of fatty acids. 29 Our data does not support the proposed protective role of cardiac TG which stores toxic lipid metabolites. 30 The apparent contradiction between studies may be attributable to our limited knowledge of how TG synthesis, hydrolysis and turnover are regulated in the heart.…”

Rodent models of diabetic cardiomyopathy

“…The mitochondrial origin of increased superoxide remains controversial because direct measurements of mitochondrial superoxide production showed no increase in STZ hearts (Herlein et al, 2009 (Lopaschuk et al, 1983;Flarsheim et al, 1996;Hattori et al, 2000;Choi et al, 2002;Zhao et al, 2006;Suarez et al, 2008). Furthermore, several studies have demonstrated increased connective tissue content in STZ-diabetic hearts, which can be attenuated by treatment of mice with the aldosterone antagonist spironolactone, suggesting that increased aldosterone action may contribute to cardiac fibrosis (Miric et al, 2001;Westermann et al, 2007;Singh et al, 2008;Ueno et al, 2008;Van Linthout et al, 2008). Cardiac angiotensin II receptor density and synthesis is increased in STZ hearts, and increased superoxide production, apoptosis and fibrosis can be inhibited, at least partially, by treatment with angiotensin receptor blockers or angiotensinconverting enzyme (ACE) inhibitors (Brown et al, 1997;Singh et al, 2008).…”