Adipose tissue ATGL modifies the cardiac lipidome in pressure-overload-induced left ventricular failure

Abstract

Adipose tissue lipolysis occurs during the development of heart failure as a consequence of chronic adrenergic stimulation. However, the impact of enhanced adipose triacylglycerol hydrolysis mediated by adipose triglyceride lipase (ATGL) on cardiac function is unclear. To investigate the role of adipose tissue lipolysis during heart failure, we generated mice with tissue-specific deletion of ATGL (atATGL-KO). atATGL-KO mice were subjected to transverse aortic constriction (TAC) to induce pressure-mediated cardiac failure. The cardiac mouse lipidome and the human plasma lipidome from healthy controls (n = 10) and patients with systolic heart failure (HFrEF, n = 13) were analyzed by MS-based shotgun lipidomics. TAC-induced increases in left ventricular mass (LVM) and diastolic LV inner diameter were significantly attenuated in atATGL-KO mice compared to wild type (wt) -mice. More importantly, atATGL-KO mice were protected against TAC-induced systolic LV failure. Perturbation of lipolysis in the adipose tissue of atATGL-KO mice resulted in the prevention of the major cardiac lipidome changes observed after TAC in wt-mice. Profound changes occurred in the lipid class of phosphatidylethanolamines (PE) in which multiple PE-species were markedly induced in failing wt-hearts, which was attenuated in atATGL-KO hearts. Moreover, selected heart failure-induced PE species in mouse hearts were also induced in plasma samples from patients with chronic heart failure. TAC-induced cardiac PE induction resulted in decreased PC/ PE-species ratios associated with increased apoptotic marker expression in failing wt-hearts, a process absent in atATGL-KO hearts. Perturbation of adipose tissue lipolysis by ATGL-deficiency ameliorated pressure-induced heart failure and the potentially deleterious cardiac lipidome changes that accompany this pathological process, namely the induction of specific PE species. Non-cardiac ATGL-mediated modulation of the cardiac lipidome may play an important role in the pathogenesis of chronic heart failure.

Atglistatin ameliorates functional decline in heart failure via adipocyte-specific inhibition of adipose triglyceride lipase

“…1G). However, consistent with previous findings (10), hearts from atATGL-KO mice had relatively preserved cardiac function (Table 2), with EF of 50% ( Fig. 1G), along with significantly improved diastolic function [ratio of early (E) to late (A) ventricular filling velocities (E/A); Fig.…”

“…*P Ͻ 0.05; †P Ͻ 0.01; ‡P Ͻ 0.001. mechanism may contribute to improved cardiac function after TAC-induced HF. However, our mice in HF do not appear to develop impaired glucose homeostasis to the extent observed in previous studies involving mice with HF (10,13), which may be due to the more rapid onset of HF in our TAC model compared with those other studies. Although we did not observe a dramatic change in the glucose tolerance of both groups of HF mice, atATGL-KO mice showed improved glucose homeostasis in comparison to WT mice.…”

“…Importantly, it has been shown that HF-induced increases in adipocyte ATGL activity contribute to the production of proinflammatory cytokines that cause systemic insulin resistance, which subsequently induces detrimental cardiac effects (13). More recently, mice with adipocyte-specific ATGL ablation (atATGL-KO mice) were shown to be protected from pressure overload-induced left ventricular (LV) failure (10). On the basis of these findings, we tested whether pharmacologically targeting adipose tissue ATGL to inhibit lipolysis was able to ameliorate functional decline in HF.…”

Of mice and men: The physiological role of adipose triglyceride lipase (ATGL)

“…Remarkably, two very recent reports also indicate a crucial role for adipocyte ATGL in protecting the failing heart. Adipocyte-specific gene deletion and acute pharmacological inhibition of ATGL prevented the progression of heart failure induced by pressure-overload [161,162]. This concept suggests that reducing the FA flux from adipose tissue during the progression of heart failure prevents cardiac lipid remodeling presumably by stabilizing cardiomyocyte membrane integrity.NLSDM patients but not muscle ATGL knockout mice exhibit progressive myopathy…”

Association between PNPLA2 Gene Polymorphisms and the Risk of Diabetic Kidney Disease in a Chinese Han Population with Type 2 Diabetes

“…Haemmerle et al reported for the first time that TG content in myocytes of ATGL-deficient (Atgl (-/-)) mice, compared with Atgl (+/+) mice, was increased by more than 20-fold [ 9 ]. Since then, many studies have been conducted to explore the relationship between ATGL and cardiac dysfunction [ 31 , 32 ]. For the kidney, accumulation of TG was increased by more than 10-fold in Atgl (-/-) mice.…”