Extracellular Signal-Regulated Kinase–Dependent Stabilization of Hepatic Low-Density Lipoprotein Receptor mRNA by Herbal Medicine Berberine

Abstract

Objective-Our recent studies identified berberine (BBR) as a novel cholesterol-lowering drug that upregulates low-density lipoprotein (LDL) receptor expression through mRNA stabilization. Here, we investigated mechanisms underlying regulatory effects of BBR on LDL receptor (LDLR) messenger. Methods and Results-We show that the extracellular signal-regulated kinase (ERK) signaling pathway is used primarily by BBR to attenuate the decay of LDLR mRNA in HepG2 cells. Using different reporter constructs, we demonstrate that BBR affects LDLR mRNA stability entirely through 3Ј untranslated region (UTR) in an ERK-dependent manner, and this stabilizing effect is more prominent in liver-derived cells than nonhepatic cell lines. In contrast to BBR, the mRNA stabilizing effect of bile acid chenodeoxycholic acid is mediated through the LDLR coding sequence, whereas the 5ЈUTR, 3ЈUTR, and the coding sequence of LDLR mRNA are all implicated in the action of phorbol 12-myristate 13-acetate. By performing UV cross-linking and SDS-PAGE, we identify 2 cytoplasmic proteins of 52 and 42 kDa that specifically bind to the LDLR 3ЈUTR in BBR-inducible and ERK-dependent manners. Key Words: LDL receptor Ⅲ berberine Ⅲ mRNA stability Ⅲ extracellular signal-regulated kinase Ⅲ 3Ј untranslated region T he expression level of liver low-density lipoprotein (LDL) receptor is one of most important regulators of human plasma LDL cholesterol (LDL-c). 1 Increased hepatic LDL receptor (LDLR) expression results in an improved clearance of LDL-c from circulation, hence directly reducing the risk of coronary heart disease. [2][3][4] Currently, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most widely used cholesterol-lowering drugs that effectively decrease the plasma concentration of LDL-c and reduce mortality and morbidity from coronary artery disease. 5,6 Our research group is interested in the discovery of new LDLR modulators from natural resources that potentially use regulatory mechanisms different but complementary to statins. Through a rationalized screening of compounds derived from Chinese herbs, we recently identified berberine (BBR), an alkaloid isolated from the herb Huanglian as a novel upregulator of hepatic LDLR expression. 7 Through studies in HepG2 and Bel-7402 hepatoma cells, we showed that BBR strongly increases LDLR mRNA expression. This action mode is totally independent of the intracellular concentration of cholesterol and the activation process of sterol regulatory element binding protein. However, BBR causes strong and sustained activation of extracellular signal-regulated kinase (ERK). Blocking ERK activation by U0126, the inhibitor of ERK upstream kinase totally prohibited the elevation of LDLR mRNA level in BBR-treated cells. Additional studies further demonstrate that BBR does not stimulate the LDLR promoter activity; instead, it increases LDLR expression by extending the half-life of LDLR mRNA through sequences present in the proximal section of the LDLR mRNA 3Ј untranslated region (UTR). In add...

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Berberine suppresses MEK/ERK-dependent Egr-1 signaling pathway and inhibits vascular smooth muscle cell regrowth after in vitro mechanical injury

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