Sort1, also known as sortilin 1, is a type I sorting receptor encoded by the SORT1 gene. It has been implicated in multiple biological processes. Sort1 is involved in lipid metabolism, such as regulating LDL-cholesterol metabolism, VLDL secretion, and PCSK9 secretion [2,3,5]. It also seems to play roles in processes like odontoblastic differentiation, extracellular vesicle secretion, cell adhesion, and may be related to inflammation, arteriosclerosis, dyslipidemia, insulin resistance, and vascular calcification [1,4,7].

In an Amish population, missense variants in SORT1 were associated with LDL-C levels, with different variants having opposite effects on LDL-C [2]. In bovine liver, fatty acids increased SORT1 abundance, leading to reduced VLDL-APOB secretion and increased hepatocyte TAG synthesis, suggesting SORT1's role in the development of fatty liver in dairy cows [3]. In multiple myeloma, SORT1 and LAMP2 were key regulators of extracellular vesicle secretion, and silencing SORT1 decreased extracellular vesicle secretion, cell adhesion, and increased sensitivity to lenalidomide [4]. In aortic valve disease, sortilin-deficient mice showed reduced valve fibrosis, calcification, and stenosis, indicating sortilin promotes these pathological changes by mediating valvular fibrosis, calcification, and a novel cell phenotype [6].

In conclusion, Sort1 has diverse essential functions in lipid metabolism, cell differentiation, and extracellular vesicle-related processes. Studies using gene-knockout or conditional-knockout mouse models and other loss-of-function experiments have revealed its significant roles in diseases such as cardiovascular diseases, fatty liver, and multiple myeloma. These findings provide insights into the biological mechanisms and potential therapeutic targets for these diseases.