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: Nan Wu, Lindsei K Sarna, Yaw L Siow, Karmin O
• Journal: American journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 300 Issue 3 Pg. R635-43 (Mar 2011) ISSN: 1522-1490 [Electronic] United States
• PMID: 21178122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Receptors, LDL
• Berberine
• Homocysteine
• Cholesterol
• Hydroxymethylglutaryl CoA Reductases
• Aspartate Aminotransferases
• Alanine Transaminase
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Alanine Transaminase (blood)
• Animals
• Aspartate Aminotransferases (blood)
• Berberine (pharmacology)
• Cholesterol (biosynthesis)
• Disease Models, Animal
• Enzyme Activation
• Hep G2 Cells
• Homocysteine (blood)
• Humans
• Hydroxymethylglutaryl CoA Reductases (genetics, metabolism)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Hyperhomocysteinemia (drug therapy, enzymology, genetics)
• Liver (drug effects, enzymology)
• Male
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• Receptors, LDL (metabolism)
• Time Factors
• Up-Regulation