Enterocyte-specific ATGL overexpression affects intestinal and systemic cholesterol homeostasis

Melanie Korbelius, Nemanja Vujić, Katharina B. Kuentzel, Sascha Obrowsky, Silvia Rainer, Guenter Haemmerle, Thomas Rülicke, Dagmar Kratky

Research output: Contribution to journalArticlepeer-review

Abstract

Enterocytes of the small intestine (SI) play an important role in maintaining systemic lipid levels by regulating dietary lipid absorption and postprandial lipoprotein secretion. An excessive amount of dietary-derived triglycerides (TGs) taken up by the apical side of enterocytes or basolaterally internalized lipoprotein remnants can be transiently stored in cytosolic lipid droplets (cLDs). As mice lacking adipose TG lipase (ATGL) in the SI display massive accumulation of cLDs but also delayed cholesterol absorption, we hypothesized that SI-specific overexpression of ATGL (Atgl iTg) might have beneficial effects on lipid homeostasis in the gut and possibly throughout the body. Here, we demonstrate that Atgl iTg mice had only modestly increased enzymatic activity despite drastically elevated Atgl mRNA levels (up to 120-fold) on chow diet, and was highly induced upon high-fat/high-cholesterol diet (HF/HCD) feeding. Atgl iTg mice showed markedly reduced intestinal TG concentrations after acute and chronic lipid challenge without affecting chylomicron TG secretion. Circulating plasma cholesterol levels were significantly lower in Atgl iTg mice under different feeding conditions, contrasting the accelerated uptake of dietary cholesterol into the circulation after HF/HCD feeding. In the fasted state, gene expression analysis revealed modulation of PPARα and liver X receptor (LXR) target genes by an increased fatty acid release, whereas the decreased plasma cholesterol concentrations in refed mice were more likely due to changes in HDL synthesis and secretion. We conclude that ATGL, in addition to its role in TG catabolism, plays a critical role in whole-body cholesterol homeostasis by modulating PPARα and LXR signaling in intestinal enterocytes.

Original languageEnglish
Article number159121
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1867
Issue number4
DOIs
Publication statusPublished - 2022 Apr
Externally publishedYes

Bibliographical note

Copyright © 2021. Published by Elsevier B.V.

Free keywords

  • Acyltransferases/genetics
  • Animals
  • Cholesterol/metabolism
  • Enterocytes/metabolism
  • Homeostasis
  • Lipase/metabolism
  • Liver X Receptors/metabolism
  • Mice
  • PPAR alpha/metabolism
  • Triglycerides/metabolism

Fingerprint

Dive into the research topics of 'Enterocyte-specific ATGL overexpression affects intestinal and systemic cholesterol homeostasis'. Together they form a unique fingerprint.

Cite this