title: Activation of sterol regulatory element binding protein and NLRP3 inflammasome in atherosclerotic lesion development in diabetic pigs.
abstract: BACKGROUND
  Aberrantly 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.forename: Shanqin
authors.initials: S
authors.lastname: Xu
authors.forename: Bingbing
authors.initials: B
authors.lastname: Jiang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cohen
authors.forename: Mengwei
authors.initials: M
authors.lastname: Zang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D048909:Diabetes Complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000737:chemistry / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000737:chemistry / Q000378:metabolism*; D013552:Swine; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D047428:Protein Kinase Inhibitors; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D019010:Vascular Cell Adhesion Molecule-1; D012694:Serine; D055372:AMP-Activated Protein Kinases