Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease associated with obesity and insulin resistance. Activation of the purinergic receptor P2Y2R has been reported to promote adipogenesis, inflammation and dyslipidemia in adipose tissues in obese mice. However, the role of P2Y2R and its mechanisms in NAFLD remain unknown. We hypothesized that P2Y2R deficiency may play a protective role in NAFLD by modulating lipid metabolism in the liver. In this study, we fed wild type and P2Y2R knockout mice with a high-fat diet (HFD) for 12 weeks and analyzed metabolic phenotypes. First, P2Y2R deficiency effectively improved insulin resistance with a reduction in body weight and plasma insulin. Second, P2Y2R deficiency attenuated hepatic lipid accumulation and injury with reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Third, P2Y2R deficiency decreased the expression of fatty acid synthesis mediators (cluster of differentiation (CD36), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1)); and increased the expression of adipose triglyceride lipase (ATGL), a lipolytic enzyme. Mechanistically, P2Y2R deficiency increased the AMP-activated protein kinase (AMPK) activity to improve mitochondrial fatty acid β-oxidation (FAO) by regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1A (CPT1A)-mediated FAO pathway. In addition, P2Y2R deficiency increased peroxisome proliferator-activated gamma co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis. Conclusively, P2Y2R deficiency ameliorated HFD-induced hepatic steatosis by enhancing FAO through AMPK signaling and PGC-1α pathway, suggesting P2Y2R as a promising therapeutic target for NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and associated with metabolic disorders such as obesity, hypertension, dyslipidemia and type 2 diabetes (T2D) [1]
To determine the role of P2Y2R in the pathogenesis of high-fat diet (HFD)-induced NAFLD, wildtype (WT) and P2Y2R knockout (KO) mice were fed with normal chow diet (NCD) or HFD for 12 weeks (Figure 1A)
The mRNA expression of P2Y2R were slightly increased in HFD-fed mice with no significance, and no P2Y2R expression was confirmed in KO mice
Summary
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and associated with metabolic disorders such as obesity, hypertension, dyslipidemia and type 2 diabetes (T2D) [1]. Several metabolic adaptation processes during the development of NAFLD are induced for the prevention of excessive fat accumulation, such as increased mitochondrial fatty acid β-oxidation (FAO). Malonyl-CoA can be an important therapeutic point for regulating lipid metabolism by acting as the first substrate for lipogenesis and an FAO inhibitor [9]. Liverspecific activation of AMPK reduces hepatic steatosis and inflammation due to promotion of FAO and inhibition of lipogenesis in mouse animal models of NAFLD [12,13]. P2Y2R plays an active role in adipogenesis and expansion of adipose tissue, lipogenesis and inflammation in white adipose tissue, thereby promoting HFD-induced obesity and insulin resistance [21,22,25]. P2Y2R deficiency plays a protective role focused on the lipogenesis and FAO signaling pathway in high-fat diet (HFD)-fed mice
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