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

Abstract

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl ester (CE) and retinyl ester (RE) and triglyceride (TG). Mice globally lacking LAL accumulate CE most prominently in the liver. The severity of the CE accumulation phenotype progresses with age and is accompanied by hepatomegaly and hepatic cholesterol crystal deposition. In contrast, hepatic TG accumulation is much less pronounced in these mice, and hepatic RE levels are even decreased. To dissect the functional role of LAL for neutral lipid ester mobilization in the liver, we generated mice specifically lacking LAL in hepatocytes (hep-LAL-ko). On a standard chow diet, hep-LAL-ko mice exhibited increased hepatic CE accumulation but unaltered TG and RE levels. Feeding the hep-LAL-ko mice a vitamin A excess/high-fat diet (VitA/HFD) further increased hepatic cholesterol levels, but hepatic TG and RE levels in these mice were lower than in control mice. Performing in vitro activity assays with lysosome-enriched fractions from livers of mice globally lacking LAL, we detected residual acid hydrolytic activities against TG and RE. Interestingly, this non-LAL acid TG hydrolytic activity was elevated in lysosome-enriched fractions from livers of hep-LAL-ko mice upon VitA/HFD feeding. In conclusion, the neutral lipid ester phenotype in livers from hep-LAL-ko mice indicates that LAL is limiting for CE turnover, but not for TG and RE turnovers. Furthermore, in vitro hydrolase activity assays revealed the existence of non-LAL acid hydrolytic activities for TG and RE. The corresponding acid lipase(s) catalyzing these reactions remains to be identified.

Lipolysis: cellular mechanisms for lipid mobilization from fat stores

“…Conversely, cells can also internalize extracellular LAL. Enzyme exchange among different cell types and tissues explains the relatively mild phenotype of hepatocyte-specific LAL-KO mice 181 and represents a potential treatment for people with Wolman's disease by enzyme replacement therapy 182 (see below).…”

Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency

“…Use of a liver-specific promoter to restrict transgene expression to hepatocytes has been shown to induce antigen-specific tolerance, thereby enhancing the safety profile. 36 While liver transplantation studies in patients with LAL-D showed some clinical efficacy, suggesting that liver is the primary organ in need of treatment, liver-specific deletion of LIPA in mice fails to manifest many aspects of LAL-D, 37 which suggests that constitutive organ expression may be needed for maximal therapeutic benefit. While we did observe increased LAL enzyme activity in the liver at P60 and P120, this did not completely correct disease phenotypes in Lipa −/− mice.…”

Lysosomal Acid Lipase Deficiency: Genetics, Screening, and Preclinical Study

“…According to the results of liver-specific Lipa deficiency, hepatic TG and RA remain unaltered in normal chow. However, an approximately 30% reduction of triglycerides in the liver in the liver-specific Lipa -cKO mice with a high-fat diet containing vitamin A at the age of five months [ 64 ]. These results clearly demonstrated that hepatic LAL plays a key role in CE metabolism in the liver, while hydrolysis of triglyceride and retinoic acid is mediated by uncharacterized lipase.…”