Intestine-specific Faf2 depletion ameliorates obesity and metabolic dysfunction-associated steatotic liver disease by impairing lipid absorption.

Fas-associated factor family member 2 (Faf2) is an endoplasmic reticulum (ER)-associated protein implicated in apolipoprotein B (ApoB) metabolism, yet its physiological role in the intestine remains unclear. To investigate this, we generated intestine-specific Faf2 knockout (Faf2-IKO) mice and fed them either a normal diet or a high-fat diet (HFD). Faf2-IKO mice exhibited reduced body weight and adiposity under both conditions, improved glucose tolerance, and protection against HFD-induced hepatic steatosis. In the intestine, Faf2 deficiency was associated with lipid droplet accumulation, intracellular retention of ApoB48, and reduced chylomicron abundance in lacteals, consistent with impaired intestinal lipoprotein handling. Faf2-IKO mice also exhibited elongation of the small intestine and villi after weaning. Despite these changes, Faf2-IKO mice showed elevated postprandial triglyceride and free fatty acid levels during lipid tolerance tests, indicating paradoxical alterations in postprandial lipid responses. Additionally, Faf2 deficiency was associated with ER dilation and increased expression of genes associated with ER-related cellular responses. Furthermore, in the livers of Faf2-IKO mice, genes that govern cholesterol homeostasis and sterol biosynthetic pathways were significantly enriched. Collectively, these findings suggest that intestinal Faf2 deficiency alters chylomicron-associated lipid handling and is associated with protection against obesity and metabolic dysfunction-associated steatotic liver disease in mice.