Hepatic iron loading in mice increases cholesterol biosynthesis.
Iron and cholesterol are both essential metabolites in mammalian systems, and too much or too little of either can have serious clinical consequences. In addition, both have been associated with steatosis and its progression, contributing, inter alia, to an increase in hepatic oxidative stress. The interaction between iron and cholesterol is unclear, with no consistent evidence emerging with respect to changes in plasma cholesterol on the basis of iron status. We sought to clarify the role of iron in lipid metabolism by studying the effects of iron status on hepatic cholesterol synthesis in mice with differing iron status. Transcripts of seven enzymes in the cholesterol biosynthesis pathway were significantly up-regulated with increasing hepatic iron (R(2) between 0.602 and 0.164), including those of the rate-limiting enzyme, 3-hydroxy-3-methylglutarate-coenzyme A reductase (Hmgcr; R(2) = 0.362, P < 0.002). Hepatic cholesterol content correlated positively with hepatic iron (R(2) = 0.255, P < 0.007). There was no significant relationship between plasma cholesterol and either hepatic cholesterol or iron (R(2) = 0.101 and 0.014, respectively). Hepatic iron did not correlate with a number of known regulators of cholesterol synthesis, including sterol-regulatory element binding factor 2 (Srebf2; R(2) = 0.015), suggesting that the increases seen in the cholesterol biosynthesis pathway are independent of Srebf2. Transcripts of genes involved in bile acid synthesis, transport, or regulation did not increase with increasing hepatic iron.


CONCLUSIONS
This study suggests that hepatic iron loading increases liver cholesterol synthesis and provides a new and potentially important additional mechanism by which iron could contribute to the development of fatty liver disease or lipotoxicity.
Graham
Ross M
RM
School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia. rmgraham@meddent.uwa.edu.au
Chua
Anita C G
AC
Carter
Kim W
KW
Delima
Roheeth D
RD
Johnstone
Daniel
D
Herbison
Carly E
CE
Firth
Martin J
MJ
O'Leary
Rebecca
R
Milward
Elizabeth A
EA
Olynyk
John K
JK
Trinder
Debbie
D
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D005234:Fatty Liver / Q000209:etiology; D007501:Iron / Q000008:administration & dosage* / Q000502:physiology*; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR
D002784:Cholesterol; D007501:Iron