Plasma cathepsin D correlates with histological classifications of fatty liver disease in adults and responds to intervention.

Sofie M A Walenbergh,Patrick Lindsey,Anita C E Vreugdenhil,Satish Kalhan,Veerle Bieghs,Ronit Shiri-Sverdlov,Patrick J Van Gorp,Marten H Hofker,Mike L J Jeurissen,Jussi Pihlajamäki,Yvonne Oligschlaeger,Tim Hendrikx,Jogchum Plat,Tom Houben,Marion J J Gijbels,Jan Willem M Greve,Sander S Rensen,Wim A Buurman,Ger H Koek

doi:10.1038/srep38278

Abstract

Non-alcoholic steatohepatitis (NASH) is characterized by liver lipid accumulation and inflammation. The mechanisms that trigger hepatic inflammation are poorly understood and subsequently, no specific non-invasive markers exist. We previously demonstrated a reduction in the plasma lysosomal enzyme, cathepsin D (CatD), in children with NASH compared to children without NASH. Recent studies have raised the concept that non-alcoholic fatty liver disease (NAFLD) in adults is distinct from children due to a different histological pattern in the liver. Yet, the link between plasma CatD to adult NASH was not examined. In the current manuscript, we investigated whether plasma CatD in adults correlates with NASH development and regression. Biopsies were histologically evaluated for inflammation and NAFLD in three complementary cohorts of adults (total n = 248). CatD and alanine aminotransferase (ALT) were measured in plasma. Opposite to our previous observations with childhood NASH, we observed increased levels of plasma CatD in patients with NASH compared to adults without hepatic inflammation. Furthermore, after surgical intervention, we found a reduction of plasma CatD compared to baseline. Our observations highlight a distinct pathophysiology between NASH in children and adults. The observation that plasma CatD correlated with NASH development and regression is promising for NASH diagnosis.

Highlights

We previously demonstrated a clear and direct association between hepatic inflammation and lysosomal cholesterol accumulation inside Kupffer cells (KCs) of low-density lipoprotein receptor knockout (Ldlr−/−) mice fed a high-fat, high-cholesterol diet[5,6,7]
body mass index (BMI), low-density lipoprotein (LDL), triglycerides and aspartate aminotransferase (AST) were all increased in subjects scored for hepatic inflammation compared to their matched controls
Plasma high-density lipoprotein (HDL) and the AST/alanine transaminase (ALT) ratio were reduced in the group with hepatic inflammation

Summary

Introduction

We previously demonstrated a clear and direct association between hepatic inflammation and lysosomal cholesterol accumulation inside Kupffer cells (KCs) of low-density lipoprotein receptor knockout (Ldlr−/−) mice fed a high-fat, high-cholesterol diet[5,6,7]. In accordance with our observation in mice, cholesterol-containing KCs were demonstrated recently in livers of NASH patients[8]. We previously detected modified levels of the lysosomal enzyme cathepsin D (CatD) in the plasma of children with NASH compared to children without hepatic inflammation[11]. As a follow-up study from our data in children, we investigated in the current paper whether plasma CatD in adults correlates with the development and regression of NASH. As the plasma CatD levels in adults with NASH were the opposite of those previously found in children with NASH11, we point toward the existence of a potential different pathophysiology between NASH in children and adults. Our data further show that CatD responds to surgical intervention, which underlines the potential clinical relevance and diagnostic value of plasma CatD in the context of NASH

Methods

Results

Conclusion