Lower plasma PCSK9 in normocholesterolemic subjects is associated with upregulated adipose tissue surface-expression of LDLR and CD36 and NLRP3 inflammasome.
Adipocytes, White
/ immunology
Adipogenesis
Adipose Tissue, White
/ immunology
Aged
Biomarkers
/ blood
CD36 Antigens
/ metabolism
Cells, Cultured
Cholesterol
/ blood
Diabetes Mellitus, Type 2
/ etiology
Down-Regulation
Female
Humans
Inflammasomes
/ metabolism
Interleukin-1beta
/ metabolism
Male
Middle Aged
NLR Family, Pyrin Domain-Containing 3 Protein
/ metabolism
Obesity
/ blood
Proprotein Convertase 9
/ blood
Receptors, LDL
/ metabolism
Risk Assessment
Risk Factors
adipose tissue and systemic inflammation
apoB-lipoproteins
cardiometabolic risk
plasma apoB-to-PCSK9
Journal
Physiological reports
ISSN: 2051-817X
Titre abrégé: Physiol Rep
Pays: United States
ID NLM: 101607800
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
19
09
2020
revised:
16
12
2020
accepted:
17
12
2020
entrez:
2
2
2021
pubmed:
3
2
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
LDL-cholesterol lowering variants that upregulate receptor uptake of LDL, such as in PCSK9 and HMGCR, are associated with diabetes via unclear mechanisms. Activation of the NLRP3 inflammasome/interleukin-1 beta (IL-1β) pathway promotes white adipose tissue (WAT) dysfunction and type 2 diabetes (T2D) and is regulated by LDL receptors (LDLR and CD36). We hypothesized that: (a) normocholesterolemic subjects with lower plasma PCSK9, identifying those with higher WAT surface-expression of LDLR and CD36, have higher activation of WAT NLRP3 inflammasome and T2D risk factors, and; (b) LDL upregulate adipocyte NLRP3 inflammasome and inhibit adipocyte function. Post hoc analysis was conducted in 27 overweight/ obese subjects with normal plasma LDL-C and measures of disposition index (DI during Botnia clamps) and postprandial fat metabolism. WAT was assessed for surface-expression of LDLR and CD36 (immunohistochemistry), protein expression (immunoblot), IL-1β secretion (AlphaLISA), and function ( Compared to subjects with higher than median plasma PCSK9, subjects with lower PCSK9 had higher WAT surface-expression of LDLR (+81%) and CD36 (+36%), WAT IL-1β secretion (+284%), plasma IL-1 receptor-antagonist (+85%), and postprandial hypertriglyceridemia, and lower WAT pro-IL-1β protein (-66%), WAT function (-62%), and DI (-28%), without group-differences in body composition, energy intake or expenditure. Adjusting for WAT LDLR or CD36 eliminated group-differences in WAT function, DI, and postprandial hypertriglyceridemia. Native LDL inhibited Simpson-Golabi Behmel-syndrome (SGBS) adipocyte differentiation and function and increased inflammation. Normocholesterolemic subjects with lower plasma PCSK9 and higher WAT surface-expression of LDLR and CD36 have higher WAT NLRP3 inflammasome activation and T2D risk factors. This may be due to LDL-induced inhibition of adipocyte function.
Sections du résumé
BACKGROUND
LDL-cholesterol lowering variants that upregulate receptor uptake of LDL, such as in PCSK9 and HMGCR, are associated with diabetes via unclear mechanisms. Activation of the NLRP3 inflammasome/interleukin-1 beta (IL-1β) pathway promotes white adipose tissue (WAT) dysfunction and type 2 diabetes (T2D) and is regulated by LDL receptors (LDLR and CD36). We hypothesized that: (a) normocholesterolemic subjects with lower plasma PCSK9, identifying those with higher WAT surface-expression of LDLR and CD36, have higher activation of WAT NLRP3 inflammasome and T2D risk factors, and; (b) LDL upregulate adipocyte NLRP3 inflammasome and inhibit adipocyte function.
METHODOLOGY
Post hoc analysis was conducted in 27 overweight/ obese subjects with normal plasma LDL-C and measures of disposition index (DI during Botnia clamps) and postprandial fat metabolism. WAT was assessed for surface-expression of LDLR and CD36 (immunohistochemistry), protein expression (immunoblot), IL-1β secretion (AlphaLISA), and function (
RESULTS
Compared to subjects with higher than median plasma PCSK9, subjects with lower PCSK9 had higher WAT surface-expression of LDLR (+81%) and CD36 (+36%), WAT IL-1β secretion (+284%), plasma IL-1 receptor-antagonist (+85%), and postprandial hypertriglyceridemia, and lower WAT pro-IL-1β protein (-66%), WAT function (-62%), and DI (-28%), without group-differences in body composition, energy intake or expenditure. Adjusting for WAT LDLR or CD36 eliminated group-differences in WAT function, DI, and postprandial hypertriglyceridemia. Native LDL inhibited Simpson-Golabi Behmel-syndrome (SGBS) adipocyte differentiation and function and increased inflammation.
CONCLUSION
Normocholesterolemic subjects with lower plasma PCSK9 and higher WAT surface-expression of LDLR and CD36 have higher WAT NLRP3 inflammasome activation and T2D risk factors. This may be due to LDL-induced inhibition of adipocyte function.
Identifiants
pubmed: 33527668
doi: 10.14814/phy2.14721
pmc: PMC7851436
doi:
Substances chimiques
Biomarkers
0
CD36 Antigens
0
CD36 protein, human
0
IL1B protein, human
0
Inflammasomes
0
Interleukin-1beta
0
LDLR protein, human
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
NLRP3 protein, human
0
Receptors, LDL
0
Cholesterol
97C5T2UQ7J
PCSK9 protein, human
EC 3.4.21.-
Proprotein Convertase 9
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14721Subventions
Organisme : CIHR
ID : 93581
Pays : Canada
Organisme : CIHR
ID : 123409
Pays : Canada
Organisme : CIHR
ID : SVB#145591
Pays : Canada
Organisme : CIHR
ID : MOP#133598
Pays : Canada
Informations de copyright
© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.
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