A Relative Deficiency of Lysosomal Acid Lypase Activity Characterizes Non-Alcoholic Fatty Liver Disease.

Francesco Tovoli,Jessica D’Amico,Fabio Piscaglia,Sergio D’Addato,Giulia Negrini,Luigi Bolondi,Giulia Tozzi,Lucia Napoli

doi:10.3390/ijms18061134

Abstract

Lysosomal acid lipase (LAL) is a key enzyme in lipid metabolism. Initial reports have suggested a role for a relative acquired LAL deficiency in non-alcoholic fatty liver disease (NAFLD)—however, it is still unclear whether this mechanism is specific for NAFLD. We aimed to determine LAL activity in a cohort of NAFLD subjects and in a control group of hepatitis C virus (HCV)-infected patients, investigating the role of liver cirrhosis. A total of 81 patients with a diagnosis of NAFLD, and 78 matched controls with HCV-related liver disease were enrolled. For each patient, LAL activity was determined on peripheral dried blood spots (DBS) and correlated with clinical and laboratory data. A subgroup analysis among cirrhotic patients was also performed. LAL activity is significantly reduced in NAFLD, compared to that in HCV patients. This finding is particularly evident in the pre-cirrhotic stage of disease. LAL activity is also correlated with platelet and white blood cell count, suggesting an analytic interference of portal-hypertension-induced pancytopenia on DBS-determined LAL activity. NAFLD is characterized by a specific deficit in LAL activity, suggesting a pathogenetic role of LAL. We propose that future studies on this topic should rely on tissue specific analyses, as peripheral blood tests are also influenced by confounding factors.

Highlights

Lysosomal acid lipase (LAL) is an enzyme that plays a pivotal role in lipid homeostasis, both in animal models and humans
We aimed to investigate the role of liver cirrhosis and identify other epidemiological, clinical, and biochemical parameters associated with LAL activity
Prevalence of liver cirrhosis was similar in the non-alcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) groups

Summary

Introduction

Lysosomal acid lipase (LAL) is an enzyme that plays a pivotal role in lipid homeostasis, both in animal models and humans. LAL hydrolyses cholesteryl esters and triglycerides internalized via receptor-mediated endocytosis of plasma lipoprotein particles (chylomicron remnants, intermediate density lipoproteins, and low-density lipoproteins) [1]. The resulting fatty acids and free cholesterol are key mediators in the homeostasis of the intra-cellular cholesterol pool [1]. Genetically determined LAL deficiency is responsible for two distinct clinical entities: Wolman disease (WD) and cholesteryl ester storage disease (CESD) [2]. WD is a severe and life-threatening paediatric condition that usually leads to death within the first year of life, due to early-onset and rapidly evolving hepatic failure. CESD is a slowly evolving condition seen among adults, characterized by a heterogeneous and polymorphic clinical pattern. Manifestations of CESD include hepatosplenomegaly, micro/macrovesicular liver steatosis, early onset cardiovascular events, and dyslipidaemia [2]

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