ABCMdb

PMID: 17058264

Tang W, Ma Y, Yu L
Plasma cholesterol is hyperresponsive to statin in ABCG5/ABCG8 transgenic mice.
Hepatology. 2006 Nov;44(5):1259-66., [PubMed]

Sentences

No. Mutations Sentence Comment

20 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His (ABCG8) D19H variant is associated with greater LDL-cholesterol lowering response to atorvastatin therapy.15 ABCG8 heterodimerizes with ABCG5 to transport cholesterol from the hepatocytes into the bile and probably from enterocytes into intestinal lumen.16-18 Mutations in either ABCG5 or ABCG8 cause sitosterolemia,19,20 an autosomal recessive sterol disorder characterized by the increased plasma and tissue levels of sitosterol and campesterol, the two major plant sterols in diet, as a result of increased dietary absorption and impaired biliary secretion of these sterols.21-23 Mice lacking abcg5/abcg8 genes recapitulate the major phenotypes of human sitosterolemia.16 On the other hand, transgenic mice overexpressing human ABCG5/ABCG8 in the liver and small intestine (G5G8Tg mice) retain much less plant sterols in the body and have a compensatory upregulation of hepatic cholesterol synthesis rates due to increased biliary secretion and reduced intestinal absorption of cholesterol.17 In human subjects, carriers of the ABCG8 D19H variant have a significantly lower ratio of plasma cholestanol/cholesterol when compared to noncarriers,24 suggesting that D19H may be a "gain of function" variant of ABCG8 gene. Login to comment 129 ABCG8 p.Asp19His Wild-type rodents are insensitive to statins, believed to be partly due to the feedback regulation of HMG-CoA reductase activity in the liver.27,28 We found in this study that lovastatin decreased plasma cholesterol in the G5G8Tg mice in spite of a much greater feedback upregulation of genes in the pathway of cholesterol synthesis, suggesting that the functional level of ABCG5/ABCG8 may also contribute to statin responsiveness, which is consistent with a clinical observation that ABCG8 D19H subjects are more responsive to atorvastatin therapy.15 Recent studies demonstrate that a SREBP-regulated gene, the proprotein convertase subtilisin/kexin type 9a (PCSK9), plays a critical role in modulating statin response in mice.37 Lovastatin administration to wild-type mice increases PCSK9 proteins in the liver through SREBP pathway, which in turn facilitates LDLR degradation.37 Disruption of PCSK9 in mice decreases plasma cholesterol and confers mice with statin hypersensitivity by raising LDLR levels.37 The molecular mechanism underlying statin hypersensitivity in G5G8Tg mice has yet to be elucidated. Login to comment