The protective effects of the \u03b23 adrenergic receptor agonist BRL37344 against liver steatosis and inflammation in a rat model of high-fat diet-induced nonalcoholic fatty liver disease (NAFLD)

Ziwen Wang,Yifan Xu,Xiaobing Wang,Min Wang,Ruifeng Wang,Zhongwei Gan,Dan Xu,Wenlong Wang,Shanshan Li,Liansheng Guo,Tieyuan Zhang

doi:10.1186/s10020-020-00164-4

Abstract

BackgroundOur objective was to investigate the efficacy of the beta-3 adrenergic receptor (β3-AR) agonist BRL37344 for the prevention of liver steatosis and inflammation associated with nonalcoholic fatty liver disease (NAFLD).MethodsFour groups were established: a control group (given a standard diet), a high-fat diet (HFD) group, an HFD + β3-AR agonist (β3-AGO) group, and an HFD + β3-AR antagonist (β3-ANT) group. All rats were fed for 12 weeks. The β3-AR agonist BRL37344 and the antagonist L748337 were administered for the last 4 weeks with Alzet micro-osmotic pumps. The rat body weights (g) were measured at the end of the 4th, 8th, and 12th weeks. At the end of the 12th week, the liver weights were measured. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed with a Hitachi automatic analyzer. The lipid levels of the triglycerides (TGs), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) and the concentrations of free fatty acids (FFAs) were also measured. An oil red O kit was used to detect lipid droplet accumulation in hepatocytes. Steatosis, ballooning degeneration and inflammation were histopathologically determined. The protein and mRNA expression levels of β3-AR, peroxisome proliferator-activated receptor-alpha (PPAR-α), peroxisome proliferator-activated receptor-gamma (PPAR-γ), mitochondrial carnitine palmitoyltransferase-1 (mCPT-1), and fatty acid translocase (FAT)/CD36 were measured by western blot analysis and RT-qPCR, respectively.ResultsAfter treatment with the β3-AR agonist BRL37344 for 4 weeks, the levels of ALT, AST, TGs, TC, LDL-C and FFAs were decreased in the NAFLD model group compared with the HFD group. Body and liver weights, liver index values and lipid droplet accumulation were lower in the HFD + β3-AGO group than in the HFD group. Decreased NAFLD activity scores (NASs) also showed that liver steatosis and inflammation were ameliorated after treatment with BRL37344. Moreover, the β3-AR antagonist L748337 reversed these effects. Additionally, the protein and gene expression levels of β3-AR, PPAR-α, and mCPT-1 were increased in the HFD + β3-AGO group, whereas those of PPAR-γ and FAT/CD36 were decreased.ConclusionThe β3-AR agonist BRL37344 is beneficial for reducing liver fat accumulation and for ameliorating liver steatosis and inflammation in NAFLD. These effects may be associated with PPARs/mCPT-1 and FAT/CD36.

Highlights

Our objective was to investigate the efficacy of the beta-3 adrenergic receptor (β3-AR) agonist BRL37344 for the prevention of liver steatosis and inflammation associated with nonalcoholic fatty liver disease (NAFLD)
Nonalcoholic fatty liver disease (NAFLD), a multifactorial clinical pathological syndrome characterized by lipid accumulation in hepatocytes and hepatocyte steatosis, includes fatty liver alone and nonalcoholic steatohepatitis (NASH); NASH can slowly progress into liver fibrosis, cirrhosis and even liver cancer (Berlanga et al 2014; Perumpail et al 2015)
Β3-AR stimulation decreased the serum Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), TGs, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and Free fatty acid (FFA) levels in the livers of model rats with HFDinduced NAFLD As summarized in Table 2, after 12 weeks, the serum ALT, AST, TGs, TC, LDL-C and FFA levels in rat livers were higher in the high-fat diet (HFD) group than in the control group

Summary

Introduction

Our objective was to investigate the efficacy of the beta-3 adrenergic receptor (β3-AR) agonist BRL37344 for the prevention of liver steatosis and inflammation associated with nonalcoholic fatty liver disease (NAFLD). The latest research (Bhatia et al 2012) has shown that NAFLD can increase the risk of mortality associated with cardiovascular disease. With the rapid development of the economy, people are consuming fewer vegetables and eating more meat. Fatty meat and animal visceral food contain a large amount of saturated fat and cholesterol. With the acceleration of work and life rhythm, people are more likely to choose fried food and increase the intake of sweets, and they are rich in saturated fat. The underlying pathogenesis of NAFLD is still not fully understood

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