Cannabinoid receptor 1 knockout alleviates hepatic steatosis by downregulating perilipin 2

Karuna Irungbam,Yuri Churin,Tomomitsu Matono,Jakob Weglage,Matthias Ocker,Dieter Glebe,Martin Hardt,Alica Koeppel,Martin Roderfeld,Elke Roeb

doi:10.1038/s41374-019-0327-5

Abstract

The endocannabinoid (EC) system has been implicated in the pathogenesis of several metabolic diseases, including nonalcoholic fatty liver disease (NAFLD). With the current study we aimed to verify the modulatory effect of endocannabinoid receptor 1 (CB1)-signaling on perilipin 2 (PLIN2)-mediated lipophagy. Here, we demonstrate that a global knockout of the cannabinoid receptor 1 gene (CB1−/−) reduced the expression of the lipid droplet binding protein PLIN2 in the livers of CB1−/− and hepatitis B surface protein (HBs)-transgenic mice, which spontaneously develop hepatic steatosis. In addition, the pharmacologic activation and antagonization of CB1 in cell culture also caused an induction or reduction of PLIN2, respectively. The decreased PLIN2 expression was associated with suppressed lipogenesis and triglyceride (TG) synthesis and enhanced autophagy as shown by increased colocalization of LC3B with lysosomal-associated membrane protein 1 (LAMP1) in HBs/CB1−/− mice. The induction of autophagy was further supported by the increased expression of LAMP1 in CB1−/− and HBs/CB1−/− mice. LAMP1 and PLIN2 were co-localized in HBs/CB1−/− indicating autophagy of cytoplasmic lipid droplets (LDs) i.e., lipophagy. Lipolysis of lipid droplets was additionally indicated by elevated expression of lysosomal acid lipase. In conclusion, these results suggest that loss of CB1 signaling leads to reduced PLIN2 abundance, which triggers lipophagy. Our new findings about the association between CB1 signaling and PLIN2 may stimulate translational studies analyzing new diagnostic and therapeutic options for NAFLD.

Highlights

Hepatic steatosis and especially its progressive form nonalcoholic steatohepatitis (NASH) are major health problems and increasing causes for liver cirrhosis and hepatocellular cancer [1]
CB1 knockout (CB1KO) mice are resistant to diet-induced obesity even though their total caloric intake is similar to that of wild type (WT) littermates, which became obese on the same diet [11]
With the current study we demonstrate that the cannabinoid receptor CB1 affected the development of hepatic steatosis by regulating perilipin 2 (PLIN2) expression in hepatitis B surface protein (HBs) transgenic mice

Summary

Introduction

Hepatic steatosis and especially its progressive form nonalcoholic steatohepatitis (NASH) are major health problems and increasing causes for liver cirrhosis and hepatocellular cancer [1]. Disturbances in lipid metabolism play a critical role in the progression of nonalcoholic fatty liver disease (NAFLD) [2]. ECs stimulate the appetite to increase energy intake, and promote lipogenesis in peripheral tissues, such as the adipose tissue, liver, and skeletal muscles, leading to obesity and fatty liver disease [7]. CB1 receptors have been reported to play a role in the development of fatty liver in Zucker rats whereas the CB1 antagonist rimonabant reduced obesity-associated hepatic steatosis and inflammatory response [10]. The treatment of obese mice with rimonabant led to a transient reduction of food intake and a marked, but sustained reduction of body weight and adiposity of these animals [11]. The mechanism by which CB1 receptor deficiency or blockade increases energy expenditure has not yet been determined

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