Feeding a Western-type high-calorie diet to a mouse model of lysosomal acid lipase deficiency (LAL-D) triggered metabolic reprogramming that modulated the homeostasis of gut-liver cholesterol, a new study published in Cells revealed. This resulted in altered bile acid composition, significant changes in the gut microbiome, reduced absorption of nutrients, and increased fecal lipid excretion.
These metabolic adaptations led to impaired bile acid synthesis, lipoprotein uptake, and cholesterol absorption, ultimately resulting in resistance to diet-induced obesity. The authors speculated that these adaptations could be protecting LAL-D cells from the lipotoxic effects of dietary lipids.
The role of lysosomal acid lipase (LAL) in diet-induced adaptations is not well known. A better understanding of the role of LAL-derived lipolytic products in maintaining gut-liver crosstalk could help better understand the pathophysiology of LAL-D, which, in turn, could pave the way for the development of new therapies.
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Here, a team of researchers led by Dagmar Kratky, professor of biochemistry at the Institute of Molecular Biology and Biochemistry of the Medical University of Graz in Austria, used LAL knock-out mice to explore the role of LAL in diet-induced adaptations.
They found that feeding mice lacking LAL a Western-type diet induced ileal fibroblast growth factor 15 (FGF15), inhibited the expression of hepatic cholesterol 7α-hydroxylase, and activated the extracellular signal-regulated kinase (ERK) phosphorylation cascade. Moreover, the animals had impaired cholesterol absorption and bile acid homeostasis. Their intestines accumulated lipids from systemic circulation, and they were resistant 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,” the authors concluded.
However, they cautioned that the extrapolation of these results to patients with LAL-D is limited due to the differences in bile acid synthesis between mice and humans.
Sachdev V, Duta-Mare M, Korbelius M, et al. Impaired bile acid metabolism and gut dysbiosis in mice lacking lysosomal acid lipase. Cells. 2021;10(10):2619. doi:10.3390/cells10102619