Surf4, also known as Surfeit locus protein 4, is a polytopic transmembrane protein mainly residing in the endoplasmic reticulum (ER) membrane. It functions as a cargo receptor, mediating protein transport from the ER to the Golgi apparatus via COPII-coated vesicles or specific vesicles, and also participates in retrograde transport from the Golgi to the ER through COPI-coated vesicles. This process is crucial for various physiological and pathophysiological processes, such as lipid metabolism, cell proliferation, and viral replication [1].

Gene knockout (KO) and conditional knockout (CKO) mouse models have significantly enhanced our understanding of Surf4's functions. In murine models, homozygous Surf4-/-mice exhibit embryonic lethality between embryonic days 3.5 and 9.5, suggesting its essential role in early embryonic development [5]. Intestinal-specific Surf4 knockdown (Surf4IKO) mice show reduced metabolism, lipid accumulation in enterocytes, and impaired fat absorption and secretion, indicating Surf4's importance in intestinal lipid absorption and chylomicron secretion [2]. Hepatic Surf4 deficiency in mice impairs serum amyloid A1 secretion and attenuates liver fibrosis [3]. Also, intestine-specific Surf4 knockout mice display ectopic lipid deposition in the small intestine and hypolipidemia, with deletion of SURF4 impeding apolipoprotein transport and lipoprotein secretion [4].

In conclusion, Surf4 is essential for protein trafficking between the ER and Golgi, playing a critical role in processes like lipid metabolism, embryonic development, and fibrosis. The KO/CKO mouse models have revealed its significance in specific disease-related biological processes, offering potential therapeutic targets for conditions such as postprandial dyslipidemia, liver fibrosis, and potentially others associated with abnormal lipid metabolism or protein secretion.