Enterocyte-specific ATGL overexpression affects intestinal and systemic cholesterol homeostasis

Area of Science:

• Lipid metabolism
• Gastroenterology
• Endocrinology

Background:

• Enterocytes in the small intestine regulate systemic lipid levels.
• Dietary lipids and lipoprotein remnants can be stored as cytosolic lipid droplets (cLDs).
• Adipose triglyceride lipase (ATGL) deficiency in the small intestine leads to cLD accumulation and delayed cholesterol absorption.

Purpose of the Study:

• To investigate the effects of small intestine-specific ATGL overexpression (Atgl iTg) on lipid homeostasis.
• To determine if enhanced ATGL activity in enterocytes benefits gut and systemic lipid management.
• To explore ATGL's role in dietary lipid absorption and lipoprotein metabolism.

Main Methods:

• Generation of Atgl iTg mice.
• Dietary challenge with high-fat/high-cholesterol diet (HF/HCD).
• Measurement of intestinal triglyceride concentrations, chylomicron secretion, and plasma cholesterol levels.
• Gene expression analysis of PPARα and liver X receptor (LXR) target genes.

Main Results:

• Atgl iTg mice exhibited reduced intestinal triglyceride levels under lipid challenge.
• Chylomicron triglyceride secretion remained unaffected.
• Plasma cholesterol levels were significantly lower in Atgl iTg mice.
• Gene expression analysis indicated modulation of PPARα and LXR signaling pathways.
• Increased fatty acid release observed in the fasted state.
• Decreased plasma cholesterol in refed mice linked to altered HDL synthesis and secretion.

Conclusions:

• Small intestine ATGL overexpression effectively reduces intestinal triglyceride accumulation.
• ATGL plays a critical role in whole-body cholesterol homeostasis beyond triglyceride catabolism.
• Modulation of PPARα and LXR signaling in enterocytes by ATGL impacts cholesterol metabolism.
• ATGL is a key regulator of both triglyceride and cholesterol balance in the gut and systemically.