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

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.

Melanoma-Derived Exosomal miR-125b-5p Educates Tumor Associated Macrophages (TAMs) by Targeting Lysosomal Acid Lipase A (LIPA)

“…As LIPA was shown to be a direct target of miR-125b-5p [48], we postulate that exosome-delivered miR-125b-5p represses LIPA in M1 macrophages. Consistently with our findings, LIPA deficiency and miR-125 overexpression in macrophages both induce identical pathways regulating proinflammatory factors and myeloid cell recruitment [29,30,49,50]. Correspondingly, LIPA knockout in melanoma-associated myeloid cells promotes cancer cell proliferation and metastasis [51].…”

“…M1 macrophages treated with exosomes showed a decreased expression of genes involved in lipid catabolic processes, including LIPA ( Figure 6C). Because others have already described that LIPA deficiency induces a proinflammatory phenotype in macrophages and hepatocytes [27][28][29][30], we analyzed if miR-125b-5p represses LIPA. The overexpression of miR-125b-5p mimics in M1 polarized macrophages strongly reduces LIPA protein compared to M1 macrophages transfected with control mimics ( Figure 6D).…”

“…Mapping against the human reference genome (hg38) and miRbase reference sequences (v22) was done using Bowtie2 (29). Read counts were calculated with the R Bioconductor package Rsamtools (http://bioconductor.org/packages/release/bioc/html/Rsamtools.html) and normalized using the DESeq2 (30) and EdgeR (31) R Bioconductor packages.…”

Hepatocyte-specific deletion of lysosomal acid lipase leads to cholesteryl ester but not triglyceride or retinyl ester accumulation

“…The identification and characterization of such acid lipase(s) will provide important insights into the endosomal/lysosomal lipid-sorting machinery. In the course of preparing this study, similar results on the phenotypes of mice lacking LAL in hepatocytes were reported by Leopold et al (44), and our report expands the characterization of the remnant, non-LAL acid hydrolytic activity in liver.…”

Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency

“…In conflict with this potential paradigm, animal studies suggest that the liver is the most physiologically important contributor to the increased de novo cholesterol biosynthesis in LALD [18]. Indeed, liver-specific LIPA deficiency is associated with dyslipidemia and increased cholesteryl ester storage [19]. Restoration of LAL activity through virusmediated transduction or transgenics in mouse models of LALD and liver-transplantation in LALD patients has proven beneficial [11,[20][21][22][23][24].…”