13 research outputs found
Effects of Coenzyme Q10 Supplementation on Exercise Performance, VO2max, and Lipid Peroxidation in Trained Cyclists
Mechanisms of Resistance of Hepatocyte Retinoid X Receptor α-Null Mice to WY-14,643-induced Hepatocyte Proliferation and Cholestasis*
Peroxisome proliferators, such as the lipid-lowering fibrates that function
as agonists for peroxisome proliferator-activated receptor α
(PPARα), induce liver tumors in rodents and may produce cholestasis in
humans. Considerable attention has focused on peroxisome proliferator-induced
hepatocellular carcinoma, a phenomenon not noted in man, whereas limited
studies examine fibrates and other therapeutic drugs that induce cholestasis,
a common finding in humans. Moreover, the mechanisms by which fibrates induce
hepatocyte proliferation and cholestasis are still not fully understood. We
have examined the role of hepatocyte retinoid X receptor α (RXRα),
an essential partner of PPARα, in modulating WY-14,643-induced
hepatocyte proliferation and cholestasis. WY-14,643 treatment induced
hepatomegaly in wild type (WT) mice that was also accompanied by induction of
the expression of cyclins D1, D3, A2, and B1 and Cdc2 as well as inhibition of
Wee 1. Such changes were either absent or greatly reduced in hepatocyte
RXRα-null mice. Furthermore, neither WY-14,643 treatment nor RXRα
deficiency affected apoptosis, indicating the importance of
PPARα/RXRα in regulating Wee 1-mediated Cdc2/cyclin B1 expression
for cells to enter into mitosis. WY-14,643 treatment also induced cholestasis
and liver injury, which is evidenced by induction of alanine aminotransferase,
alkaline phosphatase, and hepatic bile acid levels in WT mice. Hepatocyte
RXRα deficiency protected the mice from WY-14,643-induced liver injury.
WY-14,643-mediated induction of the small heterodimer partner, Mrp3, and
Cyp3a11 levels was greater in hepatocyte RXRα-null than in WT mouse
livers suggesting enhanced repression of bile acid synthesis and increased
efflux of bile acids into blood for renal excretion as well as hydroxylation
of bile acids because of hepatocyte RXRα deficiency. These data
establish a crucial role of hepatocyte RXRα in regulating
WY-14,643-mediated cell cycle progression as well as bile acid
homeostasis