Abstract
Lysosomal acid lipase (LAL) is the only known enzyme, which hydrolyzes cholesteryl esters and triacylglycerols in lysosomes of multiple cells and tissues. Here, we explored the role of LAL in brown adipose tissue (BAT). LAL-deficient (Lal−/−) mice exhibit markedly reduced UCP1 expression in BAT, modified BAT morphology with accumulation of lysosomes, and mitochondrial dysfunction, consequently leading to regular hypothermic events in mice kept at room temperature. Cold exposure resulted in reduced lipid uptake into BAT, thereby aggravating dyslipidemia and causing life threatening hypothermia in Lal−/− mice. Linking LAL as a potential regulator of lipoprotein lipase activity, we found Angptl4 mRNA expression upregulated in BAT. Our data demonstrate that LAL is critical for shuttling fatty acids derived from circulating lipoproteins to BAT during cold exposure. We conclude that inhibited lysosomal lipid hydrolysis in BAT leads to impaired thermogenesis in Lal−/− mice.
Highlights
Lysosomal acid lipase (LAL) is the only known enzyme, which hydrolyzes cholesteryl esters and triacylglycerols in lysosomes of multiple cells and tissues
Due to major metabolic adaptations caused by LAL deficiency and reduced body adiposity, we aimed to study the consequences of LAL deficiency on brown adipose tissue (BAT) function and thermogenesis
The current study provides evidence that LAL deficiency causes accumulation of lipid-laden lysosomes in BAT and that fatty acids (FA) released by acid hydrolysis serve as thermogenic activators through multiple mechanisms
Summary
Lysosomal acid lipase (LAL) is the only known enzyme, which hydrolyzes cholesteryl esters and triacylglycerols in lysosomes of multiple cells and tissues. Cold stimulates BAT via β3 adrenergic receptor signaling, which triggers the utilization of FA and glucose as substrates for thermogenesis To fuel this process, TG stored in cytosolic LD of brown adipocytes are initially catabolized via lipolysis mediated by the consecutive action of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase [15, 16]. As brown adipocytes have limited fat storage capacity, LD are continuously replenished by the supply of FA from the blood stream [15] For this purpose, food intake is increased during cold and TG (in form of circulating chylomicrons) deliver sufficient FA to activated BAT [11]. To which extent holoparticle uptake by BAT affects thermogenesis is still unclear [23] This type of substrate processing would require receptor-mediated endocytosis and lysosomal lipolytic degradation via LAL [1]
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Schedule a callMore From: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
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