SR-BI deficiency disassociates obesity from hepatic steatosis and glucose intolerance development in high fat diet-fed mice

Rick Van Der Geest,Ronald J Van Der Sluis,Miranda Van Eck,Juliet Price,Janine J Geerling,Amber B Ouweneel,Menno Hoekstra,Joya E Nahon

doi:10.1016/j.jnutbio.2020.108564

Rick Van Der Geest, Ronald J Van Der Sluis + Show 6 more

Open Access

https://doi.org/10.1016/j.jnutbio.2020.108564

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Abstract

Scavenger receptor BI (SR-BI) has been suggested to modulate adipocyte function. To uncover the potential relevance of SR-BI for the development of obesity and associated metabolic complications, we compared the metabolic phenotype of wild-type and SR-BI deficient mice fed an obesogenic diet enriched in fat. Both male and female SR-BI knockout mice gained significantly more weight as compared to their wild-type counterparts in response to 12 weeks high fat diet feeding (1.5-fold; P < .01 for genotype). Plasma free cholesterol levels were ~2-fold higher (P < .001) in SR-BI knockout mice of both genders, whilst plasma cholesteryl ester and triglyceride concentrations were only significantly elevated in males. Strikingly, the exacerbated obesity in SR-BI knockout mice was paralleled by a better glucose handling. In contrast, only SR-BI knockout mice developed atherosclerotic lesions in the aortic root, with a higher predisposition in females. Biochemical and histological studies in male mice revealed that SR-BI deficiency was associated with a reduced hepatic steatosis degree as evident from the 29% lower (P < .05) liver triglyceride levels. Relative mRNA expression levels of the glucose uptake transporter GLUT4 were increased (+47%; P < .05), whilst expression levels of the metabolic PPARgamma target genes CD36, HSL, ADIPOQ and ATGL were reduced 39%–58% (P < .01) in the context of unchanged PPARgamma expression levels in SR-BI knockout gonadal white adipose tissue. In conclusion, we have shown that SR-BI deficiency is associated with a decrease in adipocyte PPARgamma activity and a concomitant uncoupling of obesity development from hepatic steatosis and glucose intolerance development in high fat diet-fed mice.

Highlights

Scavenger receptor class B type I (SR-BI) is a membraneassociated glycoprotein that can bind native lipoprotein species such as high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoproteins (VLDL), and chylomicrons as well as their modified forms [1]
We have shown that SR-BI deficiency in high fat diet-fed mice is associated with a decrease in PPARgamma regulated genes in adipocytes, a higher predisposition to obesity and atherosclerotic lesion formation, and protection against the development of fatty liver disease and glucose intolerance (Fig. 7)
Fasting liver triglyceride stores— that can be used for VLDL production - are not primarily derived from de novo lipogenesis but rather generated via the flux of fatty acids from adipose tissue to the liver upon liberation during adipocyte triglyceride hydrolysis [34,35]

Summary

Introduction

Scavenger receptor class B type I (SR-BI) is a membraneassociated glycoprotein that can bind native lipoprotein species such as high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoproteins (VLDL), and chylomicrons as well as their modified forms [1]. Lack of proper SR-BI functionality is consistently associated with glucocorticoid insufficiency, that is, a diminished ability of the adrenals to produce respectively cortisol in humans and corticosterone in mice [5,7,8,9]. SR-BI deficiency markedly stimulates the development of atherosclerotic lesions in mice [10] and several rare variants are associated with a significantly higher (atherosclerotic) cardiovascular disease frequency in humans [6,11]

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