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

Sumihiko Hagita,Masanori Aikawa,Maximillian A Rogers,Tan Pham,Elena Aikawa,Andrew K Mlynarchik,Jennifer R Wen

doi:10.1038/s41598-018-27416-y

Sumihiko Hagita, Masanori Aikawa + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-27416-y

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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.

Highlights

Dysfunctional lipid handling and metabolism are associated with obesity and metabolic disease[1,2], which in turn are major risk factors for cardiovascular disease[3]
While the association of Sortilin to cardiovascular disease is established, whether Sortilin plays a role in adipose tissue function, body weight gain, and factors shared by both cardiovascular disease and obesity, like Niemann-Pick type C1-Like 1 (NPC1L1), is unclear
Female low-density lipoprotein receptor-deficient (Ldlr−/−)Sort1−/− mice on both normal chow (NC) and high-fat/ high cholesterol (HF/HC) diet had significantly lower body weight gain starting at three-weeks-in that was maintained through the remainder of the 15-week feeding (Fig. 1a,b)

Summary

Introduction

Dysfunctional lipid handling and metabolism are associated with obesity and metabolic disease[1,2], which in turn are major risk factors for cardiovascular disease[3]. Supporting a role of intestinal cholesterol absorption in adipose tissue and cardiovascular disease, ezetimibe treatment or Npc1l1 deficiency in mice on a high-fat diet, reduces body weight and adipogenesis[9,10]. While the association of Sortilin to cardiovascular disease is established, whether Sortilin plays a role in adipose tissue function, body weight gain, and factors shared by both cardiovascular disease and obesity, like NPC1L1, is unclear. Sort[1] deficiency generated by deleting 41 codons in exon 14, resulting in a reading frame disruption, reduced body weight gain and visceral fat in diet-induced obesity male C57BL/6 mice; without altering viability, fertility, or showing any gross abnormalities[21]. Given the strong connection of Sortilin to cardiovascular disease, we sought to assess if under atherosclerosis-related conditions, Sort[1] deficiency alters adipose tissue function, weight gain, and NPC1L1-mediated cholesterol absorption in male and female mice

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Conclusion