A gut-derived hormone regulates cholesterol metabolism

Area of Science:

• Endocrinology
• Metabolic Regulation
• Molecular Biology

Background:

• Cholesterol homeostasis relies on coordinated intestinal absorption and hepatic synthesis.
• Mechanisms regulating these opposing cholesterol processes are not fully understood.

Purpose of the Study:

• To identify novel factors regulating cholesterol homeostasis.
• To elucidate the molecular mechanisms linking intestinal cholesterol absorption to hepatic cholesterol synthesis.

Main Methods:

• Identification and characterization of a novel hormone, Cholesin.
• Investigation of Cholesin's binding to the G-protein-coupled receptor GPR146.
• Analysis of downstream signaling pathways, including PKA and SREBP2.

Main Results:

• Cholesin is secreted by the intestine upon cholesterol absorption.
• Cholesin inhibits hepatic de novo cholesterol synthesis by antagonizing PKA signaling.
• The Cholesin-GPR146 axis suppresses SREBP2-mediated cholesterol synthesis.

Conclusions:

• The Cholesin-GPR146 axis is a key mediator of feedback regulation between intestinal cholesterol absorption and hepatic synthesis.
• Cholesin represents a potential therapeutic target for hypercholesterolemia and atherosclerosis.