Pioglitazone reduces tumor necrosis factor-alpha serum concentration and mRNA expression of adipose tissue in hypercholesterolemic rabbits.
BACKGROUND
Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine involved in atherogenesis. Adipose tissue is an important source of endogenous TNF-alpha production. Pioglitazone, a member of the thiazolidinediones (TZDs), has anti-inflammatory and anti-atherogenic properties, while underlying mechanism has not been fully elucidated. The aim of this study was to evaluate the effect of pioglitazone on TNF-alpha serum concentration and mRNA expressions of subcutaneous adipose tissue in hypercholesterolemic rabbits.


METHODS
Ten rabbits fed with high-cholesterol diet for 8 weeks were randomly divided into two groups: (1) high cholesterol group (n=5): maintained high cholesterol diet for 4 weeks; (2) pioglitazone group (n=5): the same cholesterol diet plus pioglitazone (3 mg/kg/day) for 4 weeks. Control group (n=5) was fed with normal diet for 12 weeks. Subcutaneous adipose tissue was collected for RNA analysis. The direct effect of pioglitazone on TNF-alpha release was assayed in primary rabbit adipocytes. TNF-alpha levels in serum and adipocytes culture supernatant were measured by ELISA. RT-PCR was used to evaluate TNF-alpha mRNA expressions in adipose tissue and adipocytes.


RESULTS
Compared with control group, rabbits fed with high cholesterol diet showed significantly higher levels of serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and TNF-alpha. Though having no effect on serum glucose level and lipid profile, pioglitazone administration significantly reduced circulating TNF-alpha concentrations, which were positively correlated with TNF-alpha mRNA expressions of adipose tissue (r=0.53, P<0.01). Pioglitazone dose-dependently inhibited lipopolysaccharide (LPS)-induced TNF-alpha secretion and mRNA expression in cultured adipocytes.


CONCLUSIONS
Pioglitazone significantly reduced serum TNF-alpha level in hypercholesterolemic rabbits independent of its metabolic actions, which may at least partly be due to its direct inhibition of TNF-alpha expression and secretion of adipocytes. This may help to explain the mechanism by which pioglitazone exert anti-atherosclerotic effects.
Wu
Zhi-hong
ZH
Department of Cardiology, The Second Xiangya Hospital of Central South University, Middle Ren-Min road No 139, Changsha, Hunan 410011, PR China.
Zhao
Shui-ping
SP
Chu
Luo-xiang
LX
Ye
Hui-jun
HJ
D017667:Adipocytes / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000097:blood / Q000494:pharmacology; D008078:Cholesterol, LDL / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D050151:Subcutaneous Fat / Q000166:cytology / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000235:genetics*
D001786:Blood Glucose; D002791:Cholesterol, Dietary; D008078:Cholesterol, LDL; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077205:Pioglitazone