Lead nitrate-induced development of hypercholesterolemia in rats: sterol-independent gene regulation of hepatic enzymes responsible for cholesterol homeostasis.
Changes in the gene expressions of hepatic enzymes responsible for cholesterol homeostasis were examined during the process of lead nitrate (LN)-induced development of hypercholesterolemia in male rats. Total cholesterol levels in the liver and serum were significantly increased at 3-72 h and 12-72 h, respectively, after LN-treatment (100 micromol/kg, i.v.). Despite the development of hypercholesterolemia, the genes for hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and other enzymes (FPPS, farnesyl diphosphate synthase; SQS, squalene synthase; CYP51, lanosterol 14alpha-demethylase) responsible for cholesterol biosynthesis were activated at 3-24 h and 12-18 h, respectively. On the other hand, the gene expression of cholesterol 7alpha-hydroxylase (CYP7A1), a catabolic enzyme of cholesterol, was remarkably suppressed at 3-72 h. The gene expression levels of cytokines interleukin-1beta (IL-1beta) and TNF-alpha, which activate the HMGR gene and suppress the CYP7A1 gene, were significantly increased at 1-3 h and 3-24 h, respectively. Furthermore, gene activation of SREBP-2, a gene activator of several cholesterogenic enzymes, occurred before the gene activations of FPPS, SQS and CYP51. This is the first report demonstrating sterol-independent gene regulation of hepatic enzymes responsible for cholesterol homeostasis in LN-treated male rats. The mechanisms for the altered-gene expressions of hepatic enzymes in LN-treated rats are discussed.
Kojima
Misaki
M
Laboratory of Animal Gene Function, Department of Physiology and Gene Regulation, National Institute of Agrobiological Sciences, Kannondai 2-1-2, Tsukuba 305-8602, Japan.
Masui
Toshimitsu
T
Nemoto
Kiyomitsu
K
Degawa
Masakuni
M
D019883:Alkyl and Aryl Transferases / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis / Q000235:genetics; D006937:Hypercholesterolemia / Q000139:chemically induced* / Q000201:enzymology; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D007854:Lead / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009566:Nitrates / Q000008:administration & dosage / Q000633:toxicity*; D010088:Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058886:Sterol 14-Demethylase; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D009566:Nitrates; D012333:RNA, Messenger; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D007854:Lead; C017461:lead nitrate; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D010088:Oxidoreductases; D006903:Hydroxymethylglutaryl CoA Reductases; D058886:Sterol 14-Demethylase; D002790:Cholesterol 7-alpha-Hydroxylase; D019883:Alkyl and Aryl Transferases; C086466:farnesylgeranyl diphosphate synthase; D013186:Farnesyl-Diphosphate Farnesyltransferase