Abstract

Bile acid (BA) sequestrants, lipid-lowering agents, may be prescribed as a monotherapy or combination therapy to reduce the risk of coronary artery disease. Over 33% of adults in the United States use complementary and alternative medicine strategies, and we recently reported that grape seed procyanidin extract (GSPE) reduces enterohepatic BA recirculation as a means to reduce serum triglyceride (TG) levels. The current study was therefore designed to assess the effects on BA, cholesterol and TG homeostatic gene expression following co-administration with GSPE and the BA sequestrant, cholestyramine (CHY). Eight-week old male C57BL/6 mice were treated for 4 weeks with either a control or 2% CHY-supplemented diet, after which, they were administered vehicle or GSPE for 14 hours. Liver and intestines were harvested and gene expression was analyzed. BA, cholesterol, non-esterified fatty acid and TG levels were also analyzed in serum and feces. Results reveal that GSPE treatment alone, and co-administration with CHY, regulates BA, cholesterol and TG metabolism differently than CHY administration alone. Notably, GSPE decreased intestinal apical sodium-dependent bile acid transporter (Asbt) gene expression, while CHY significantly induced expression. Administration with GSPE or CHY robustly induced hepatic BA biosynthetic gene expression, especially cholesterol 7α-hydroxylase (Cyp7a1), compared to control, while co-administration further enhanced expression. Treatment with CHY induced both intestinal and hepatic cholesterologenic gene expression, while co-administration with GSPE attenuated the CHY-induced increase in the liver but not intestine. CHY also induced hepatic lipogenic gene expression, which was attenuated by co-administration with GSPE. Consequently, a 25% decrease in serum TG levels was observed in the CHY+GSPE group, compared to the CHY group. Collectively, this study presents novel evidence demonstrating that GSPE provides additive and complementary efficacy as a lipid-lowering combination therapy in conjunction with CHY by attenuating hepatic cholesterol synthesis, enhancing BA biosynthesis and decreasing lipogenesis, which warrants further investigation.

Highlights

  • One in every four deaths in the US is attributable to cardiovascular disease (CVD) [1]

  • The dose of procyanidins used is onefifth of the no-observed-adverse-effect level (NOAEL) described for grape seed procyanidin extract (GSPE) in male rats [43] and we previously showed that this dose reduces serum TG levels in normolipidemic C57BL/6 mice [39, 40, 44] and fructose-induced hypertriglyceridemic rats [41]

  • GSPE and cholestyramine differentially modulate bile acid uptake and transport Our first aim was to determine the effects of GSPE, CHY and co-administration with CHY +GSPE on intestinal Bile acid (BA) uptake and transporter gene expression in order to elucidate any differences and/or interactions at the transcriptional level

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Summary

Introduction

One in every four deaths in the US is attributable to cardiovascular disease (CVD) [1]. Regulation of two controllable CVD-associated risk factors, namely serum cholesterol and triglyceride levels, is tightly linked to BA homeostasis. BAs, in addition to their established role in digestion, function as signaling molecules with systemic endocrine effects. BAs regulate their own uptake and synthesis, and cholesterol and triglyceride homeostasis [2,3,4]. Modifications in BA-activated signaling pathways have become an attractive therapeutic target for treating hypercholesterolemia and hypertriglyceridemia. Identifying potential gene regulatory interactions between pharmaceutical interventions and natural treatments used in the amelioration of risk factors associated with CVD is important

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