Activation of Sterol Regulatory Element Binding Protein and NLRP3 Inflammasome in Atherosclerotic Lesion Development in Diabetic Pigs

Yu Li,Bingbing Jiang,Shanqin Xu,Mengwei Zang,Richard A Cohen,Karin Jandeleit-Dahm

doi:10.1371/journal.pone.0067532

Abstract

BackgroundAberrantly elevated sterol regulatory element binding protein (SREBP), the lipogenic transcription factor, contributes to the development of fatty liver and insulin resistance in animals. Our recent studies have discovered that AMP-activated protein kinase (AMPK) phosphorylates SREBP at Ser-327 and inhibits its activity, represses SREBP-dependent lipogenesis, and thereby ameliorates hepatic steatosis and atherosclerosis in insulin-resistant LDLR−/− mice. Chronic inflammation and activation of NLRP3 inflammasome have been implicated in atherosclerosis and fatty liver disease. However, whether SREBP is involved in vascular lipid accumulation and inflammation in atherosclerosis remains largely unknown.Principal FindingsThe preclinical study with aortic pouch biopsy specimens from humans with atherosclerosis and diabetes shows intense immunostaining for SREBP-1 and the inflammatory marker VCAM-1 in atherosclerotic plaques. The cleavage processing of SREBP-1 and -2 and expression of their target genes are increased in the well-established porcine model of diabetes and atherosclerosis, which develops human-like, complex atherosclerotic plaques. Immunostaining analysis indicates an elevation in SREBP-1 that is primarily localized in endothelial cells and in infiltrated macrophages within fatty streaks, fibrous caps with necrotic cores, and cholesterol crystals in advanced lesions. Moreover, concomitant suppression of NAD-dependent deacetylase SIRT1 and AMPK is observed in atherosclerotic pigs, which leads to the proteolytic activation of SREBP-1 by diminishing the deacetylation and Ser-372 phosphorylation of SREBP-1. Aberrantly elevated NLRP3 inflammasome markers are evidenced by increased expression of inflammasome components including NLPR3, ASC, and IL-1β. The increase in SREBP-1 activity and IL-1β production in lesions is associated with vascular inflammation and endothelial dysfunction in atherosclerotic pig aorta, as demonstrated by the induction of NF-κB, VCAM-1, iNOS, and COX-2, as well as by the repression of eNOS.ConclusionsThese translational studies provide in vivo evidence that the dysregulation of SIRT1-AMPK-SREBP and stimulation of NLRP3 inflammasome may contribute to vascular lipid deposition and inflammation in atherosclerosis.

Highlights

Atherosclerosis, a chronic inflammatory disease, is the most common cause of cardiovascular death [1,2]
These translational studies provide in vivo evidence that the dysregulation of SIRT1-AMPactivated protein kinase (AMPK)-sterol regulatory element binding protein (SREBP) and stimulation of NLRP3 inflammasome may contribute to vascular lipid deposition and inflammation in atherosclerosis
To gain insight into the clinical relevance of SREBP-1 to vascular inflammation in human atherosclerosis, aortic pouch biopsy specimens were obtained from patients with diabetes and coronary artery atherosclerosis and immunostained for SREBP-1, a-smooth muscle actin (a-SM-actin), and vascular cell adhesion molecule-1 (VCAM-1), a critical endothelial-leukocyte adhesion molecule in atherogenesis [6,16]

Summary

Introduction

Atherosclerosis, a chronic inflammatory disease, is the most common cause of cardiovascular death [1,2]. Non-alcoholic fatty liver disease and atherosclerotic disease in humans have common pathological features such as the deposition of excess lipids in the liver or on the vascular wall, little is known about the relationship between SREBP and vascular dysfunction in atherosclerosis This translational study provides the first evidence for an elevation of SREBP in atherosclerotic lesions in humans with diabetes. Elevated sterol regulatory element binding protein (SREBP), the lipogenic transcription factor, contributes to the development of fatty liver and insulin resistance in animals. Our recent studies have discovered that AMPactivated protein kinase (AMPK) phosphorylates SREBP at Ser-327 and inhibits its activity, represses SREBP-dependent lipogenesis, and thereby ameliorates hepatic steatosis and atherosclerosis in insulin-resistant LDLR2/2 mice. Whether SREBP is involved in vascular lipid accumulation and inflammation in atherosclerosis remains largely unknown

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