Cathepsin D regulates lipid metabolism in murine steatohepatitis

Tom Houben,Marion J J Gijbels,Ronit Shiri-Sverdlov,Yvonne Oligschlaeger,Frank G Schaap,Patrick J Van Gorp,Albert V Bitorina,Silvia Friedrichs,Dieter Lütjohann,Jogchum Plat,Tim Hendrikx,Sofie M A Walenbergh,Marten H Hofker

doi:10.1038/s41598-017-03796-5

Abstract

Due to the obesity epidemic, non-alcoholic steatohepatitis (NASH) is a prevalent liver disease, characterized by fat accumulation and inflammation of the liver. However, due to a lack of mechanistic insight, diagnostic and therapeutic options for NASH are poor. Recent evidence has indicated cathepsin D (CTSD), a lysosomal enzyme, as a marker for NASH. Here, we investigated the function of CTSD in NASH by using an in vivo and in vitro model. In addition to diminished hepatic inflammation, inhibition of CTSD activity dramatically improved lipid metabolism, as demonstrated by decreased plasma and liver levels of both cholesterol and triglycerides. Mechanistically, CTSD inhibition resulted in an increased conversion of cholesterol into bile acids and an elevated excretion of bile acids via the feces, indicating that CTSD influences lipid metabolism. Consistent with these findings, treating Wt BMDMs with PepA in vitro showed a similar decrease in inflammation and an analogous effect on cholesterol metabolism. Conclusion: CTSD is a key player in the development of hepatic inflammation and dyslipidemia. Therefore, aiming at the inhibition of the activity of CTSD may lead to novel treatments to combat NASH.

Highlights

Due to the increasing obesity epidemic, non-alcoholic fatty liver disease (NAFLD) has emerged as the most important liver disease in the world[1]
To determine the effect of the proteolytic inhibition of cathepsin D (CTSD) on hepatic inflammation, immunohistochemical stainings were performed on liver sections for the inflammatory cell markers Mac-1, CD3, CD68 and F4/80
We show for the first time that the lysosomal enzyme CTSD is a key player in the pathogenesis of non-alcoholic steatohepatitis (NASH)

Summary

Introduction

Due to the increasing obesity epidemic, non-alcoholic fatty liver disease (NAFLD) has emerged as the most important liver disease in the world[1]. Proteolytic inhibition of CTSD dramatically improved lipid and lipoprotein metabolism, which is demonstrated by decreased plasma and liver levels of both cholesterol and triglycerides. Quantification of all immunohistochemical stainings showed no effect of one week PepA treatment on hepatic inflammation in Ldlr−/− mice on HFC diet at histological level (Fig. 1B–D and Supplementary Table S1).

Results

Conclusion