Impaired Bile Acid Metabolism and Gut Dysbiosis in Mice Lacking Lysosomal Acid Lipase

Abstract

Lysosomal acid lipase (LAL) is the sole enzyme known to be responsible for the hydrolysis of cholesteryl esters and triglycerides at an acidic pH in lysosomes, resulting in the release of unesterified cholesterol and free fatty acids. However, the role of LAL in diet-induced adaptations is largely unexplored. In this study, we demonstrate that feeding a Western-type diet to Lal-deficient (LAL-KO) mice triggers metabolic reprogramming that modulates gut-liver cholesterol homeostasis. Induction of ileal fibroblast growth factor 15 (three-fold), absence of hepatic cholesterol 7α-hydroxylase expression, and activation of the ERK phosphorylation cascade results in altered bile acid composition, substantial changes in the gut microbiome, reduced nutrient absorption by 40%, and two-fold increased fecal lipid excretion in LAL-KO mice. These metabolic adaptations lead to impaired bile acid synthesis, lipoprotein uptake, and cholesterol absorption and ultimately to the resistance of LAL-KO mice to diet-induced obesity. Our results indicate that LAL-derived lipolytic products might be important metabolic effectors in the maintenance of whole-body lipid homeostasis.

Impact of (intestinal) LAL deficiency on lipid metabolism and macrophage infiltration

“…The increased number of immune cells, especially macrophages, in various organs such as liver, lung or SI of LAL KO mice already suggested that they play a crucial role in the pathogenesis of LAL-D [ 32 ]. Our present findings demonstrate that infiltrating macrophages are responsible for the severe lipid accumulation in LAL KO mice, predominantly incorporating lipids from the circulation, as recently suggested [ 31 ]. We have identified a macrophage subclass that is very similar to LAMs and DAM and whose most prominent marker is TREM2 [ 43 , 45 ].…”

“…Since macrophages of the lamina propria are located in close proximity to blood vessels, lipids taken up from the basolateral side (circulation) are more likely to contribute to the formation of lipid-filled macrophages than dietary lipids. Consistent with our data from chow diet-fed LAL KO mice, LAL KO mice fed a Western-type diet had increased basolateral lipid uptake, which was associated with impaired dietary lipid absorption and higher fecal lipid loss [ 31 ]. Lipid-filled macrophages are mainly present in the duodenum of LAL KO mice, which is in agreement with the fact that basolateral lipid uptake is more pronounced in the proximal part of the SI and gradually decreases in the jejunum and ileum [ 23 , 31 , 52 ].…”

“…In addition to the previously described prominent lipid accumulation in macrophages of the lamina propria of the SI [ 31 , 32 ], we observed lipid-containing lysosomes in duodenal enterocytes of mice globally lacking LAL ( Figure 1 A), indicating that enterocyte LAL may play a pivotal role in the metabolism of dietary lipids. Acid CE hydrolase (CEH) and TG hydrolase (TGH) activities, reflecting the enzymatic action of LAL, were reduced by ∼ 80% and 30%, respectively, in enterocytes isolated from LAL KO mice ( Figure 1 B,C).…”

Regional Differences in the Small Intestinal Proteome of Control Mice and of Mice Lacking Lysosomal Acid Lipase

“…One of the most affected tissues in patients suffering from LAL deficiency (LAL-D) is the SI, in which massive lipid accumulation causes gastrointestinal symptoms, such as vomiting, diarrhea with steatorrhea, and abdominal distension . We and others have shown that the SI of Lal-deficient (KO) mice is severely affected due to pronounced macrophage infiltration. − Interestingly, we observed that macrophages, not enterocytes, are the main cell type that accumulated lipids in these mice, suggesting that LAL does not play a crucial role in lipid metabolism in enterocytes . The infiltrating macrophages in the duodenum of Lal KO mice displayed a triggering receptor expressed on myeloid cells-2 (Trem2)-like gene signature previously identified in lipid-associated macrophages (LAMs) and disease-associated macrophages …”

Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease

“…LAL is present in all cell types with the exception of erythrocytes ( Grabowski et al, 2019 ), and participates in multiple physiological processes in different tissues. Additional roles for LAL have been elucidated in thermogenesis ( Duta-Mare et al, 2018 ; Fischer et al, 2021 ; Fischer et al, 2022 ), bile acid metabolism with effects on the gut microbiome ( Sachdev et al, 2021 ), insulin sensitivity ( Radović et al, 2016 ), and retinoic acid metabolism ( Grumet et al, 2016 ).…”