Transcriptional control of intestinal cholesterol absorption, adipose energy expenditure and lipid handling by Sortilin

Abstract

The sorting receptor Sortilin functions in the regulation of glucose and lipid metabolism. Dysfunctional lipid uptake, storage, and metabolism contribute to several major human diseases including atherosclerosis and obesity. Sortilin associates with cardiovascular disease; however, the role of Sortilin in adipose tissue and lipid metabolism remains unclear. Here we show that in the low-density lipoprotein receptor-deficient (Ldlr−/−) atherosclerosis model, Sortilin deficiency (Sort1−/−) in female mice suppresses Niemann-Pick type C1-Like 1 (Npc1l1) mRNA levels, reduces body and white adipose tissue weight, and improves brown adipose tissue function partially via transcriptional downregulation of Krüppel-like factor 4 and Liver X receptor. Female Ldlr−/−Sort1−/− mice on a high-fat/cholesterol diet had elevated plasma Fibroblast growth factor 21 and Adiponectin, an adipokine that when reduced is associated with obesity and cardiovascular disease-related factors. Additionally, Sort1 deficiency suppressed cholesterol absorption in both female mice ex vivo intestinal tissue and human colon Caco-2 cells in a similar manner to treatment with the NPC1L1 inhibitor ezetimibe. Together our findings support a novel role of Sortilin in energy regulation and lipid homeostasis in female mice, which may be a potential therapeutic target for obesity and cardiovascular disease.

Sortilin in Glucose Homeostasis: From Accessory Protein to Key Player?

“…Furthermore, studies on double knockout mice for the low-density lipoprotein receptor (Ldlr-/-, an atherosclerosis model) and sortilin (Sort1-/-) have confirmed the previous observations showing that sortilin is crucial for lipid homeostasis by suppressing intestinal cholesterol absorption mostly in female mice (Hagita et al, 2018). It is important to note that some contradictory results were obtained using another so-called sort1-/- model (Li et al, 2017a).…”

“…It was observed that suppression of sortilin gene does not affect diet-induced obesity and glucose uptake from adipose tissue and skeletal muscle. A closer look of both Sort1-/- model mice used showed that the first studies were performed using a mouse in which the exon 14th of the sortilin gene was deleted, leading to the expression of a soluble sortilin receptor (Rabinowich et al, 2015; Hagita et al, 2018).…”

“…The other deletion was done on the second exon deleting almost all of the sortilin protein (Li et al, 2017a). Similarly to the first Sort1-/- model described (Rabinowich et al, 2015; Hagita et al, 2018), NT-deficient mice are resistant to DIO, hepatic steatosis and insulin resistance (Li et al, 2016). In order to explain such differences between sortilin deficient mice models, it is possible to argue that the expression of a circulating soluble form of the receptor, is able to buffer the NT in the blood stream and also potentially the other sortilin-interacting peptides (Quistgaard et al, 2014).…”

Sortilin levels are associated with peripheral arterial disease in type 2 diabetic subjects

“…Numerous evidence suggests that sortilin is implicated in the pathogenesis of many inflammatory and metabolic diseases, including T2DM and atherosclerotic complications of diabetes [31]. In addition, sortilin has been shown to be an energetic regulator of lipid metabolism [44]. No definitive data about the role of sortilin in atherosclerosis and diabetes, however, are available.…”

An (Auto)Taxing Effort to Mechanistically Link Obesity and Calcific Aortic Valve Disease

“…Linking risk factors of these diseases could identify molecular mechanisms that can be therapeutically targeted to lower cardiovascular risk in the increasing worldwide obese patient population. By supporting a connection of calcification genetic risk factors to obesity, we previously showed that a genetic risk factor for vascular calcification—sortilin—also contributed to obesity in a female mouse model of vascular disease ( 4 ). Whether similar connections between obesity and CAVD genetic risk factors exist is largely unknown.…”