Surf4 (Surfeit Locus Protein 4) Deficiency Reduces Intestinal Lipid Absorption and Secretion and Decreases Metabolism in Mice

Abstract

Background: Postprandial dyslipidemia is a causative risk factor for cardiovascular disease. The majority of absorbed dietary lipids are packaged into chylomicron and then delivered to circulation. Previous studies showed that Surf4 (surfeit locus protein 4) mediates very low-density lipoprotein secretion from hepatocytes. Silencing hepatic Surf4 markedly reduces the development of atherosclerosis in different mouse models of atherosclerosis without causing hepatic steatosis. However, the role of Surf4 in chylomicron secretion is unknown.

Methods: We developed inducible intestinal-specific Surf4 knockdown mice (Surf4^IKO) using Vil1Cre-ER^T2 and Surf4^flox mice. Metabolic cages were used to monitor mouse metabolism. Enzymatic kits were employed to measure serum and tissue lipid levels. The expression of target genes was detected by qRT-PCR and Western Blot. Transmission electron microscopy and radiolabeled oleic acid were used to assess the structure of enterocytes and intestinal lipid absorption and secretion, respectively. Proteomics was performed to determine changes in protein expression in serum and jejunum.

Results: Surf4^IKO mice, especially male Surf4^IKO mice, displayed significant body weight loss, increased mortality, and reduced metabolism. Surf4^IKO mice exhibited lipid accumulation in enterocytes and impaired fat absorption and secretion. Lipid droplets and small lipid vacuoles were accumulated in the cytosol and the endoplasmic reticulum lumen of the enterocytes of Surf4^IKO mice, respectively. Surf4 colocalized with apoB and co-immunoprecipitated with apoB48 in differentiated Caco-2 cells. Intestinal Surf4 deficiency also significantly reduced serum triglyceride, cholesterol, and free fatty acid levels in mice. Proteomics data revealed that diverse pathways were altered in Surf4^IKO mice. In addition, Surf4^IKO mice had mild liver damage, decreased liver size and weight, and reduced hepatic triglyceride levels.

Conclusions: Our findings demonstrate that intestinal Surf4 plays an essential role in lipid absorption and chylomicron secretion and suggest that the therapeutic use of Surf4 inhibition requires highly cell/tissue-specific targeting.

Keywords: COPII; chylomicrons; enterocytes; liver; sex difference.