Pioglitazone stimulates apolipoprotein A-I production without affecting HDL removal in HepG2 cells: involvement of PPAR-alpha.
OBJECTIVE
Pioglitazone, an antihyperglycemic drug, increases plasma high-density lipoprotein (HDL)-cholesterol in patients with type 2 diabetes. The mechanisms by which pioglitazone regulate HDL levels are not clear. This study examined the effect of pioglitazone on hepatocyte apolipoprotein AI (apoA-I) and apoA-II production and HDL-protein/cholesterol ester uptake.


RESULTS
In human hepatoblastoma (HepG2) cells, pioglitazone, dose-dependently (0.5 to 10 micromol/L), increased the de novo synthesis (up to 45%), secretion (up to 44%), and mRNA expression (up to 59%) of apoA-I. Pioglitazone also increased apoA-II de novo synthesis (up to 73%) and mRNA expression (up to 129%). Pioglitazone did not affect the uptake of HDL3-protein or HDL3-cholesterol ester in HepG2 cells. The pioglitazone-induced apoA-I lipoprotein particles increased cholesterol efflux from THP-1 macrophages. The pioglitazone-induced apoA-I secretion or mRNA expression by the HepG2 cells was abrogated with the suppression of PPAR-alpha by small interfering RNA or a specific inhibitor of PPAR-alpha, MK886.


CONCLUSIONS
The data indicate that pioglitazone increases HDL by stimulating the de novo hepatic synthesis of apoA-I without affecting hepatic HDL-protein or HDL-cholesterol removal. We suggest that pioglitazone-mediated hepatic activation of PPAR-alpha may be one of the mechanisms of action of pioglitazone to raise hepatic apoA-I and HDL.
Qin
Shucun
S
Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, Long Beach, California 90822, USA.
Liu
Tianjiao
T
Kamanna
Vaijinath S
VS
Kashyap
Moti L
ML
D016632:Apolipoprotein A-I / Q000187:drug effects* / Q000378:metabolism; D016633:Apolipoprotein A-II / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000187:drug effects* / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation
D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D007004:Hypoglycemic Agents; D008075:Lipoproteins, HDL; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077205:Pioglitazone