Abstract
Hyperlipidemia is a major risk factor for metabolic disorders and cardiovascular injury. The excessive deposition of saturated fatty acids in the heart leads to chronic cardiac inflammation, which in turn causes myocardial damage and systolic dysfunction. However, the effective suppression of cardiac inflammation has emerged as a new strategy to reduce the impact of hyperlipidemia on cardiovascular disease. In this study, we identified a novel monomer, known as LuHui Derivative (LHD), which reduced the serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and reduced lipid deposition in cardiomyocytes. In addition, LHD treatment improved cardiac function, reduced hyperlipidemia-induced inflammatory infiltration in cardiomyocytes and suppressed the release of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). From a mechanistic perspective, cluster of differentiation 36 (CD36), an important cell surface receptor, was identified as a downstream target following the LHD treatment of palmitic acid-induced inflammation in cardiomyocytes. LHD specifically binds the pocket containing the regulatory sites of RNA methylation in the fat mass and obesity-associated (FTO) protein that is responsible for elevated intracellular m6A levels. Moreover, the overexpression of the N6-methyladenosine (m6A) demethylase FTO markedly increased CD36 expression and suppressed the anti-inflammatory effects of LHD. Conversely, loss-of-function of FTO inhibited palmitic acid-induced cardiac inflammation and altered CD36 expression by diminishing the stability of CD36 mRNA. Overall, our results provide evidence for the crucial role of LHD in fatty acid-induced cardiomyocyte inflammation and present a new strategy for the treatment of hyperlipidemia and its complications.
Highlights
Dyslipidemia causes damage to multiple tissues and organs and is a critical risk factor for atherosclerotic cardiovascular disease (Liu et al, 2017)
Cardiac echocardiography showed that, compared with the CTL group, the administration of high-fat diet (HFD) clearly decreased the EF% and FS%; in contrast, LuHui Derivative (LHD) treatment significantly mitigated the hyperlipidemia-induced cardiac systolic and diastolic dysfunction (Figures 1E,F). These results indicated that LHD treatment altered the hyperlipidemia-associated changes in lipids and cardiac function in vivo
The results showed that Palmitic acid (PA) stimulation increased the expression of most metabolismrelated enzymes; the most significant change occurred in cluster of differentiation 36 (CD36) expression and this increase was notably inhibited by LHD treatment (Figures 2E,F)
Summary
Dyslipidemia causes damage to multiple tissues and organs and is a critical risk factor for atherosclerotic cardiovascular disease (Liu et al, 2017). The evidence suggests that chronic systemic hyperlipidemia contributes to nonalcoholic fatty liver disease, diabetes, muscle and heart tissue damage, and the inflammatory response (Nicholls and Lundman, 2004; Ertunc and Hotamisligil, 2016; Healy et al., 2016; Ralston et al, 2017). FTO was shown to play an essential role in the regulation of food intake and adipose synthesis (Hess et al, 2013; Ben-Haim et al, 2015). It has not been confirmed if FTO is a promising target for the treatment of hyperlipidemia-induced cardiomyocyte inflammation
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