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.
Highlights
As cholesterol is a major component of biological membranes and a substrate for the generation of steroid hormones and bile acids, its synthesis and uptake are tightly regulated [1]
This study shows that Lysosomal acid lipase (LAL)-KO mice fed a high-calorie diet (Western-type diet, WTD) display profound changes in enterohepatic bile acids (BA) metabolism and the intestinal microbiome compared to wild-type (WT) mice
LAL-KO mice already had lower body weight before we challenged them with WTD and the difference in weight gain increased during the 6-week feeding period (Figure 1a)
Summary
As cholesterol is a major component of biological membranes and a substrate for the generation of steroid hormones and bile acids, its synthesis and uptake are tightly regulated [1]. Cholesterol and triglycerides (TG) transported by apolipoprotein B-containing lipoproteins (i.e., chylomicron (CM) remnants and low-density lipoproteins (LDL)) are taken up into the cell by receptor-mediated endocytosis and processed in lysosomes [2]. The critical importance of LAL-mediated lipid processing is evident in patients suffering from LAL deficiency (LAL-D). Disease severity varies largely depending on the type of mutation and is determined by the absence or presence of residual LAL activity, leading to either Wolman disease (WD) or CE storage disease (CESD), respectively. Whereas patients affected by WD are unlikely to survive beyond 6 months of age predominantly due to malabsorption and failure to thrive, CESD patients can reach adulthood but suffer from severe dyslipidemia, accelerated atherosclerosis, early cardiovascular events, and liver failure [3]. The approval of enzyme replacement therapy in 2015 dramatically changed the treatment strategy for LAL-D from supportive care to sustained improvement in the clinical outcomes, with some therapeutic and significant pharmacoeconomic limitations [10]
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