Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation

Christina Leopold,Madalina Duta-Mare,Vinay Sachdev,Madeleine Goeritzer,Lisa Katharina Maresch,Dagmar Kolb,Helga Reicher,Bettina Wagner,Tatjana Stojakovic,Thomas Ruelicke,Guenter Haemmerle,Gerald Hoefler,Wolfgang Sattler,Dagmar Kratky

doi:10.1016/j.bbalip.2019.01.007

Abstract

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CE) and triglycerides (TG) to generate fatty acids (FA) and cholesterol. LAL deficiency (LAL-D) in both humans and mice leads to hepatomegaly, hypercholesterolemia, and shortened life span. Despite its essential role in lysosomal neutral lipid catabolism, the cell type-specific contribution of LAL to disease progression is still elusive. To investigate the role of LAL in the liver in more detail and to exclude the contribution of LAL in macrophages, we generated hepatocyte-specific LAL-deficient mice (Liv-Lipa−/−) and fed them either chow or high fat/high cholesterol diets (HF/HCD). Comparable to systemic LAL-D, Liv-Lipa−/− mice were resistant to diet-induced obesity independent of food intake, movement, and energy expenditure. Reduced body weight gain was mainly due to reduced white adipose tissue depots. Furthermore, Liv-Lipa−/− mice exhibited improved glucose clearance during glucose and insulin tolerance tests compared to control mice. Analysis of hepatic lipid content revealed a massive reduction of TG, whereas CE concentrations were markedly increased, leading to CE crystal formation in the livers of Liv-Lipa−/− mice. Elevated plasma transaminase activities, increased pro-inflammatory cytokines and chemokines as well as hepatic macrophage infiltration indicated liver inflammation. Our data provide evidence that hepatocyte-specific LAL deficiency is sufficient to alter whole-body lipid and energy homeostasis in mice. We conclude that hepatic LAL plays a pivotal role by preventing liver damage and maintaining lipid and energy homeostasis, especially during high lipid availability.

Highlights

The liver is an essential metabolic organ, and hepatic energy metabolism is tightly controlled by multiple nutrient, hormonal, and neuronal signals, which regulate glucose, lipid, and amino acid metabolism
Defective lysosomal lipolysis in global Lipa−/− mice with hepatomegaly, microvesicular steatosis and infiltration of Kupffer cells leading to formation of “fatty lysosomes” [4] rendered global Lipa−/− mice impossible to study the contribution of hepatocytes to the severe liver phenotype
Lipa mRNA expression and Lysosomal acid lipase (LAL) activity were reduced by 99% and 70%, respectively, in Liv-Lipa−/− mice compared to controls (Fig. 1B, C)

Summary

Introduction

The liver is an essential metabolic organ, and hepatic energy metabolism is tightly controlled by multiple nutrient, hormonal, and neuronal signals, which regulate glucose, lipid, and amino acid metabolism. The liver utilizes glucose as metabolic fuel and converts glucose into fatty acids (FA). After their release from white adipose tissue (WAT) or dietary intake, hepatocytes can take up FA from the circulation. The absence of LAL results in lysosomal accumulation of CE and TG, associated with reduced generation of unesterified FA and cholesterol, which are important molecules for catabolic, anabolic, and signaling pathways [6]. The majority of patients exhibit hepatic steatosis in the absence of substantial inflammation or fibrosis [16]. 10– 30% of patients with NAFLD develop NASH [15], characterized by varying degrees of hepatic inflammation, ballooning of hepatocytes, and fibrosis in addition to liver steatosis

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Conclusion