Liver X Receptor Inverse Agonist SR9243 Suppresses Nonalcoholic Steatohepatitis Intrahepatic Inflammation and Fibrosis.

Peng Huang,Lin-feng Mao,Benson Kaluba,Zhi-peng Zhang,Xiao-lin Jiang,Shi Chang,Fei-zhou Huang,Xiao-feng Tang

doi:10.1155/2018/8071093

Abstract

Abnormal metabolism of cholesterol may be a contributing factor in nonalcoholic steatohepatitis (NASH) pathogenesis. Accumulating evidence has shown that liver X receptor (LXR) is closely related to intrahepatic inflammation and fibrosis. In this study, we evaluated the effects of a novel liver-specific LXR inverse agonist, SR9243, on antifibrosis in NASH mice. A high-cholesterol diet was employed to induce NASH in BALB/c mice by either carbon tetrachloride (CCL4) administration or bile-duct ligation (BDL). Once NASH was induced, mice were treated with SR9243 for one month by intraperitoneal (i.p.) injection. Liver tissues were collected to determine the degree of fibrosis and intrahepatic inflammation via pathological examination and QPCR; serum was collected to analyze the plasma lipid levels and liver function by clinical biochemistry. The mice developed hepatic steatosis, severe hepatic inflammation, and fibrosis by BDL or CCL4. Treatment with SR9243 significantly reduced the severity of hepatic inflammation and ameliorated hepatic fibrosis; simultaneously, body weight, serum glucose, and plasma lipid levels were controlled effectively. Our data demonstrate that SR9243 exerts an antifibrotic and anti-inflammatory effect in NASH mice; hence these findings highly suggest that LXR inverse agonist could be therapeutically important in NASH treatment.

Highlights

Nonalcoholic steatohepatitis (NASH) is considered as leading cause of hepatitis nonviral liver cirrhosis and hepatocellular carcinoma [1, 2]
Since accumulating evidences have proved that efficiency in both lipid transport and delivery seems to be a crucial factor in transitioning from hepatic steatosis to NASH, high-calorie diets with excessive fats and carbohydrates can cause this imbalance leading to nonalcoholic fatty liver disease (NAFLD) and in some cases progression to NASH; in addition, intrahepatic cholestasis caused by biliary obstruction can lead to NASH [5, 6]
SR9243 Significantly Decreased Liver Fibrosis Induced by bile-duct ligation (BDL) and CCL4

Summary

Introduction

Nonalcoholic steatohepatitis (NASH) is considered as leading cause of hepatitis nonviral liver cirrhosis and hepatocellular carcinoma [1, 2]. In the development of NASH, nonalcoholic fatty liver disease (NAFLD) is the first step and is characterized by hepatic steatosis which is caused by an imbalance between fat/influx of energy and utilization [3, 4]. Since accumulating evidences have proved that efficiency in both lipid transport and delivery seems to be a crucial factor in transitioning from hepatic steatosis to NASH, high-calorie diets with excessive fats and carbohydrates can cause this imbalance leading to NAFLD and in some cases progression to NASH; in addition, intrahepatic cholestasis caused by biliary obstruction can lead to NASH [5, 6]. The potential of LXR as a therapeutic target in the pathogenesis of metabolic diseases by regulating metabolic and inflammatory pathways has recently been realized [9]. Known synthetic LXR agonists like GW3965 and T0901317 have previously been reported

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Conclusion