Inducible global knockout of surfeit locus protein 4 in adult mice results in hypolipidemia, intestinal lipid accumulation, liver injury, and increased mortality.

Abstract

Surfeit locus protein 4 (SURF4) acts as a cargo receptor to mediate endoplasmic reticulum export of various cargos. We have shown that SURF4 is essential for secretion of hepatic very low-density lipoprotein and intestinal chylomicron. Knockdown of hepatic Surf4 also significantly reduces the development of atherosclerosis and liver fibrosis without causing overt liver damage. However, constitutive global Surf4 knockout results in embryonic lethality. To further understand the physiological role of Surf4, we generated tamoxifen-inducible global Surf4 knockout mice. We found that conditional knockout of Surf4 in adult mice (Surf4^ig-ko) significantly reduced mouse body weight. Male and female Surf4^ig-ko mice died approximately 30 and 50 days after tamoxifen administration, respectively. Triglyceride secretion and serum levels of total cholesterol, triglycerides, free fatty acids, apolipoprotein B-100, and apolipoprotein-48 were significantly reduced in Surf4^ig-ko mice compared with Surf4^flox mice. Proteomics analysis of mouse serum samples revealed 308 proteins with significantly altered expression in Surf4^ig-ko mice that have unique functions and are involved in various biological processes. In addition, Surf4^ig-ko mice exhibited lipid accumulation in the intestine but not in the liver. However, in Surf4^ig-ko mice, liver weight was significantly reduced, and serum transaminase activity was significantly increased, indicating liver damage. Therefore, SURF4 is essential for survival in adult mice, suggesting that the therapeutic use of SURF4 requires precise tissue/cell type-specific targeting.