Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis.
Nonalcoholic steatohepatitis (NASH) is a common feature of the metabolic syndrome and toxic reactions to pharmacological drugs. Tamoxifen, (TMX) a widely used anti-breast cancer drug, can induce NASH and changes in plasma cholesterol levels through mechanisms that are unclear. We studied primary actions of TMX using a short-term treatment (5 days) that induces microvesicular hepatic steatosis and marked hypercholesterolemia in male rats. Using a combined approach of gene expression profiling and NMR-based metabolite analysis, we found that TMX-treated livers have increased saturated fatty acid content despite changes in gene expression, indicating decreased de novo lipogenesis and increased fatty acid oxidation. Our results show that TMX predominantly down-regulates FAS expression and activity as indicated by the accumulation of malonyl-CoA, a known inhibitor of mitochondrial beta-oxidation. In the face of a continued supply of exogenous free fatty acids, the blockade of fatty acid oxidation produced by elevated malonyl-CoA is likely to be the major factor leading to steatosis. Use of a combination of metabolomic and transcriptomic analysis has allowed us to identify mechanisms underlying important metabolic side effects of a widely prescribed drug. Given the broader importance of hepatic steatosis, the novel molecular mechanism revealed in this study should be examined in other forms of steatosis and nonalcoholic steatohepatitis.
Lelliott
Christopher J
CJ
Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
López
Miguel
M
Curtis
R Keira
RK
Parker
Nadeene
N
Laudes
Matthias
M
Yeo
Giles
G
Jimenez-Liñan
Mercedes
M
Grosse
Johannes
J
Saha
Asish K
AK
Wiggins
David
D
Hauton
David
D
Brand
Martin D
MD
O'Rahilly
Stephen
S
Griffin
Julian L
JL
Gibbons
Geoffrey F
GF
Vidal-Puig
Antonio
A
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004435:Eating / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis*; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008316:Malonyl Coenzyme A / Q000032:analysis; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013629:Tamoxifen / Q000494:pharmacology*
D005227:Fatty Acids; D012333:RNA, Messenger; D013629:Tamoxifen; D008316:Malonyl Coenzyme A; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D064429:Fatty Acid Synthases