Tribbles Homolog 3 Promotes Foam Cell Formation Associated with Decreased Proinflammatory Cytokine Production in Macrophages: Evidence for Reciprocal Regulation of Cholesterol Uptake and Inflammation

Autor: William Timothy Garvey, Wei Zhang, Elizabeth Ma, Dennis Steverson, Ling Tian, Yuchang Fu
Rok vydání: 2016
Předmět:
0301 basic medicine
medicine.medical_specialty
Time Factors
Endocrinology
Diabetes and Metabolism
Glucose uptake
Interleukin-1beta
Down-Regulation
Cell Cycle Proteins
Inflammation
Protein Serine-Threonine Kinases
030204 cardiovascular system & hematology
Fatty Acid-Binding Proteins
Transfection
Proinflammatory cytokine
Mice
03 medical and health sciences
0302 clinical medicine
Insulin resistance
Downregulation and upregulation
Cell Line
Tumor
Internal medicine
Internal Medicine
medicine
Animals
Humans
Macrophage
Foam cell
Tumor Necrosis Factor-alpha
business.industry
Original Articles
Atherosclerosis
medicine.disease
Up-Regulation
Lipoproteins
LDL
Repressor Proteins
Cholesterol
RAW 264.7 Cells
030104 developmental biology
Endocrinology
Cytokines
lipids (amino acids
peptides
and proteins)
Tumor necrosis factor alpha
Inflammation Mediators
medicine.symptom
business
Foam Cells
Zdroj: Metabolic Syndrome and Related Disorders. 14:7-15
ISSN: 1557-8518
1540-4196
DOI: 10.1089/met.2015.0037
Popis: Insulin resistance is central in the pathophysiology of cardiometabolic disease; however, common mechanisms that explain the parallel development of both type 2 diabetes and atherosclerosis have not been elucidated. We have previously shown that tribbles homolog 3 (TRB3) can exert a chronic pathophysiological role in promoting insulin resistance and also has an acute physiological role to alternatively regulate glucose uptake in fat and muscle during short-term fasting and nutrient excess. Since TRB3 is expressed in human atherosclerotic plaques, we explored its role in foam cell formation to assess its potential contribution to atherogenesis.We have used human THP-1 monocytes, which transition to lipid-laden macrophage foam cells when exposed to oxidized low-density lipoprotein (ox-LDL).We first observed that TRB3 was upregulated by more than twofold (P 0.01) within 24 hr of treatment with ox-LDL. To determine whether TRB3 actively participated in foam cell formation, we overexpressed TRB3 in THP-1 monocytes and found that this led to a 1.5-fold increase in cholesterol accumulation after 48 hr (P 0.01), compared with controls. At the same time, TRB3 overexpression suppressed inflammation in macrophages as evidenced by reduced expression and secretion of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) (both P 0.01).(1) TRB3 is upregulated in macrophages upon treatment with ox-LDL; (2) TRB3 promotes lipid accumulation and suppresses cytokine expression; and (3) inflammation and foam cell formation can be reciprocally regulated, and TRB3 orients the macrophage to assume a more primary role for lipid accumulation while maintaining a secondary role as an inflammatory immune cell.
Databáze: OpenAIRE
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