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Review
. 2019 Aug 14;25(30):4172-4180.
doi: 10.3748/wjg.v25.i30.4172.

Reduced lysosomal acid lipase activity: A new marker of liver disease severity across the clinical continuum of non-alcoholic fatty liver disease?

Francesco Baratta  1 , Daniele Pastori  1 , Domenico Ferro  1 , Giovanna Carluccio  1 , Giulia Tozzi  2 , Francesco Angelico  3 , Francesco Violi  1 , Maria Del Ben  1
Affiliations
Review

Reduced lysosomal acid lipase activity: A new marker of liver disease severity across the clinical continuum of non-alcoholic fatty liver disease?

Francesco Baratta et al. World J Gastroenterol. .

Abstract

Lysosomal acid lipase (LAL) plays a key role in intracellular lipid metabolism. Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage, as observed in two recessive autosomal genetic diseases, Wolman disease and Cholesterol ester storage disease. Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency. By contrast, few reliable data are available on the modulation of LAL activity in vivo and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene. In the last few years, a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease (NAFLD), suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease. Patients with NAFLD show a significant, progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis. Among cirrhosis of different etiologies, those with cryptogenic cirrhosis show the most significant reductions of LAL activity. These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD. Moreover, the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting.

Keywords: Cholesterol ester storage disease; Cirrhosis; Lysosomal acid lipase; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Wolman disease.

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Conflict of interest statement

Conflict-of-interest statement: No potential conflicts of interest. No financial support.

Figures

Figure 1
Figure 1
LAL activity reduction in the spectrum of NAFLD. LAL: Lysosomal acid lipase; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; CESD: Cholesterol esters storage disease.
Figure 2
Figure 2
Changes of hepatic lipid metabolism in lysosomal acid lipase deficiency. Reduced lysosomal acid lipase activity causes lysosomal lipid accumulation and reduction of free fatty acids and cholesterol in cytosol. This reduction influences numerous gene transcriptions via transcription factors such as liver X receptors and steroid regulation binding proteins, resulting in higher expression of low-density lipoprotein receptor, acetyl-coenzyme A acetyltransferase, and 3-idrossi-3-metilglutaril-coenzima A reductase and in a lower expression of ATP-binding cassette A1. These changes result in amplified lysosomal lipid accumulation, increased serum very low-density lipoproteins, and decreased serum high-density lipoprotein. LAL: Lysosomal acid lipase; ACAT: Acetyl-coenzyme A acetyltransferase; HMGCoA: 3-Idrossi-3-metilglutaril-coenzima A; LXRs: Liver X receptors; SREBPs: Steroid regulation binding proteins; ABCA1: ATP-binding cassette A1; LDL: Low-density lipoprotein; VLDL: Very low-density lipoproteins; HDL: High-density lipoprotein; LDL-r: Low-density lipoprotein receptor.
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