Oleanolic Acid Regulates Blood Lipid Metabolism By Inhibiting The Expression Of Liver PGC-1β

Hyperlipidemia is a common chronic disease, and a major risk factor for cardiovascular diseases including atherosclerosis. Its clinical features includes abnormally elevated levels of one or multiple kinds of lipids and/or lipoproteins in blood.Hyperlipidemia is classified into three types according to the categories of lipids elevated:hypercholesterolemia, hypertriglyceridemia and combined hyperlipidemia. As the major site for de novo synthesis of fatty acids and cholesterols, liver plays an important role in the lipid homeostasis. Fatty acids synthesized in liver are converted into triglycerides and secreted as very low density lipoproteins (VLDL), which transport fatty acids to the circulation system for the use or storage in peripheral tissues. Cholesterols synthesized in the liver are also transported to other tissues via VLDL, to be used as synthetic materials for steroid hormones and cell membranes. However, excess production of fatty acids and cholesterols may lead to a variety of lipid disorders, such as hyperlipidemia and result in the pathogenesis of cardiovascular diseases, such as atherosclerosis.The lipogenic process in liver is primarily regulated by the lipogenic transcription factors, sterol regulatory element-binding proteins (SREBPs). SREBPs regulate lipogenesis by activating the expression of their target genes, such as acetyl CoA carboxylase (ACCl), fatty acid synthase (FAS), glycerin-3-phosphate acyltransferase (GPAT), and so on. SREBP1c and SREBP2 respectively control the synthesis of fatty acids and cholesterol, while SREBPla is a potent activator of both. As the important regulatory factors for lipogensis, SREBPs have been shown to interact with multiple nuclear transcriptional factors (TFs) and cofactors in regulating the expression of lipogenic genes, including peroxisome proliferator-activated recepton co-activator-1β (PGC-1β). More importantly, PGC-1β quickly responses to the external environmental changes, and selectively interacts with TFs, such as SREBP, liver-X receptor (LXR), and forkhead box a2 (Foxa2) to regulate different metabolic processes. For example, it can activate the hepatic lipogenesis and lipoprotein secretion, which lead to hyperglycemia.Oleanolic acid (OA) is a triterpenoid that exists widely in fruits, vegetables and medicinal herbs. Oleanolic acid possesses various promising pharmacological properties, such as hepatoprotion, anti-inflammation, hypolipid and so on. For example, pomegranate flower, which contains OA, improves glucose intolerance, fatty liver and excess cardiac lipid accumulation in Zucker diabetic fatty rats. OA ameliorates atherosclerosis in ApoE knockout mice. In addition, modulation of SREBP1c-mediated pathways has been demonstrated to contribute to OA-elicited improvement of fructose-induced fatty liver in rats. However, the molecular mechanism underlying hypolipidemic effect of is still poorly understood. Sine PGC-1β plays an important role in the process of lipid metabolism in mouse liver, we hypothesized that PGC-1β may serve as a target for OA action and mediate its therapeutic effects through modulating lipoprotein metabolism.We studied the hypolipidemic effect of OA both in vitro and in vivo. For the in vitro assay, OA inhibited PGC-1β expression at both the mRNA and protein levels. For the in vivo assay, PGC-1β expression level was also significantly reduced in mouse liver when mice were treated with OA for 4 hours. The serum triglyceride (TG) and low density lipoprotein cholesterol (LDL-C) levels were also lower following a single dose of OA administration. However, serum total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels remained unchanged throughout this study. After tail-vein injection of PGC-1β siRNA which led to the liver-specific knockdown of PGC-1β, the hypolipidemic effect of OA was partially impaired. In addition, the phosphorylation of P38 MAPK was induced after OA treated. Pretreated SB203580 (a P38 inhibitor) remarkably abolished the effect of OA on PGC-1β in mouse primary hepatocytes.In conclusion, OA reduces serum TG and LDL-C through activating P38 MAPK phosphorylation and inhibiting PGC-1β expression in liver, thus suppressing fatty acid synthesis. Our results demonstrate that PGC-1β is an important target for the hypolipidemic effect of OA. This study provides a solid theoretical and experimental basis for clinical application of OA.