title: Regulation of hepatic cholesterol biosynthesis by berberine during hyperhomocysteinemia.
abstract: Hyperhomocysteinemia, an elevation of blood homocysteine levels, is a metabolic disorder associated with dysfunction of multiple organs. We previously demonstrated that hyperhomocysteinemia stimulated hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase leading to hepatic lipid accumulation and liver injury. The liver plays an important role in cholesterol biosynthesis and overall homeostasis. HMG-CoA reductase catalyzes the rate-limiting step in cholesterol biosynthesis. Hepatic HMG-CoA reductase is a major target for lowering cholesterol levels in patients with hypercholesterolemia. The aim of the present study was to examine the effect of berberine, a plant-derived alkaloid, on hepatic cholesterol biosynthesis in hyperhomocysteinemic rats and to identify the underlying mechanism. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 4 wk. HMG-CoA reductase activity was markedly elevated in the liver of hyperhomocysteinemic rats, which was accompanied by hepatic lipid accumulation. Activation of HMG-CoA reductase was caused by an increase in its gene expression and a reduction in its phosphorylation (an inactive form of the enzyme). Treatment of hyperhomocysteinemic rats with berberine for 5 days inhibited HMG-CoA reductase activity and reduced hepatic cholesterol content. Such an inhibitory effect was mediated by increased phosphorylation of HMG-CoA reductase. Berberine treatment also improved liver function. These results suggest that berberine regulates hepatic cholesterol biosynthesis via increased phosphorylation of HMG-CoA reductase. Berberine may be therapeutically useful for the management of cholesterol homeostasis.
authors.affiliation: St. Boniface Hospital Research Centre, Winnipeg, Canada.
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.forename: Lindsei K
authors.initials: LK
authors.lastname: Sarna
authors.forename: Yaw L
authors.initials: YL
authors.lastname: Siow
authors.forename: Karmin
authors.initials: K
authors.lastname: O
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001599:Berberine / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D056945:Hep G2 Cells; D006710:Homocysteine / Q000097:blood; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020138:Hyperhomocysteinemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D001599:Berberine; D006710:Homocysteine; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D055372:AMP-Activated Protein Kinases