Deletion of Perilipin 5 Protects Against Hepatic Injury in Nonalcoholic Fatty Liver Disease via Missing Inflammasome Activation.

Anastasia Asimakopoulou,Ralf Weiskirchen,Eva M Buhl,Josef Van Helden,Kathrin M Engel,Nikolaus Gassler,Stavroula Kalampoka,Thilo Bracht,Barbara Sitek,Jürgen Schiller,Manuela Pinoé-Schmidt

doi:10.3390/cells9061346

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver diseases with an increasing prevalence due to rising rates of obesity, metabolic syndrome and type II diabetes. Untreated NAFLD may progress to steatohepatitis (NASH) and ultimately liver cirrhosis. NAFLD is characterized by lipid accumulation, and when sufficient excess lipids are obtained, irreversible liver injury may follow. Perilipin 5 (PLIN5), a known lipid droplet coating protein and triglyceride metabolism regulator, is highly expressed in oxidatively modified tissues but it is still unclear how it affects NAFLD/NASH progress. We here studied how PLIN5 affects NAFLD development induced by a 30-week high-fat diet (HFD) administration in wild type and PLIN5 knock out (Plin5−/−) mice. The disruption of PLIN5 induced differences in lipid metabolism during HFD feeding and was associated with reduced hepatic fat accumulation. Surprisingly, Plin5−/− mice showed mitigated activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, leading to minor hepatic damage. We conclude that PLIN5 is a pleiotropic regulator of hepatic homeostasis in NASH development. Targeting the PLIN5 expression appears critical for protecting the liver from inflammatory activation during chronic NAFLD.

Highlights

Nonalcoholic fatty liver disease (NAFLD) has become one of the leading causes of chronic liver diseases in Western societies and is associated with obesity, insulin resistance, type II diabetes mellitus, hyperlipidaemia and metabolic syndrome [1]
We found a relation of Perilipin 5 (PLIN5) to inflammation in human liver samples obtained from patients suffering from hepatocellular carcinoma (HCC)
The integrity of wild type (WT) and Plin5−/− heterozygous or homozygous litters used in our NAFLD studies were confirmed with conventional PCR on genomic DNA (Figure 1A) and Western blot analysis visualizing protein levels in liver and heart tissue (Figure 1B)

Summary

Introduction

NAFLD has become one of the leading causes of chronic liver diseases in Western societies and is associated with obesity, insulin resistance, type II diabetes mellitus, hyperlipidaemia and metabolic syndrome [1]. The pathophysiology of NAFLD is quite complex. Despite the growing prevalence of NAFLD and its progress to NASH, liver fibrosis and cirrhosis and/or hepatocellular carcinoma, the underlying mechanisms of NAFLD are largely unknown. NAFLD is characterized mainly as simple steatosis present in more than 5% of hepatocytes [2]. Lipotoxicity during chronic untreated NAFLD endorses a ballooning degeneration of hepatocytes and inflammation. The histological establishment of fat accumulation, ballooned hepatocytes and inflammatory recruitment are essential conditions for the diagnosis and grading of NASH [3]

Methods

Results

Discussion

Conclusion