Abstract
NF-E2-related factor 2 (Nrf2) is a transcription factor that is activated by oxidative stress and electrophiles that regulates the expression of numerous detoxifying and antioxidant genes. Previous studies have shown that Nrf2 protects the liver from xenobiotic toxicity; however, whether Nrf2 plays a role in lipid homeostasis in liver is not known. Accordingly, wild-type and Nrf2-null mice were fed a high-fat diet (HFD) for up to 4 weeks. Hepatic gene expression and lipid profiles were analyzed for changes in fatty acid, triglyceride, and cholesterol status. It is interesting to note that HFD reduced the mRNA expression of Nrf2 and its target genes in wild-type mice. The mRNA expression of lipogenic and cholesterologenic transcriptional factors and their target genes, such as sterol regulatory element-binding proteins 1c and 2, fatty acid synthase, acetyl-CoA carboxylase 1, fatty acid elongase, 3-hydroxy-3-methylglutaryl coenzyme A synthase and reductase, and low-density lipoprotein receptor mRNA expression were higher in Nrf2-null mice compared with wild-type mice after feeding a HFD, suggesting that Nrf2 may suppress these pathways. Hepatic triglycerides and cholesterol levels were not different between genotypes, whereas concentrations of hepatic free fatty acid and malondialdehyde equivalents were higher in Nrf2-null mice compared with wild-type mice 4 weeks after HFD feeding. Overall, these results suggest that Nrf2 inhibits lipid accumulation and oxidative stress in mouse liver after feeding a HFD, probably by interfering with lipogenic and cholesterologenic pathways.
Footnotes
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This work was supported by National Institutes of Health Grants ES09649, ES09716, ES07079, and RR021940.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.135822.
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ABBREVIATIONS: NASH, nonalcoholic steatohepatitis; SREBP, sterol regulatory element-binding protein; FAS, fatty acid synthase; ACC-1, acetyl-CoA carboxylase 1; FAE, fatty acid elongase; SCD1, stearoyl-CoA desaturase-1; PPAR, peroxisome proliferator-activated receptor; AOX, acyl-CoA oxidase; Cpt-1, carnitine palmitoyltransferase-1; Cyp4a, cytochrome P450 4a; Cyp4a10, cytochrome P450 4a10; Cyp4a14, cytochrome P450 4a14; LDL, low-density lipoprotein; LXR, liver X receptor; Cyp7a1, cholesterol 7-α hydroxylase; Cyp8b1, sterol 12-α hydroxylase; MTP, microsomal triglyceride transfer protein; VLDL, very low-density lipoprotein; Nrf2, NF-E2-related factor 2; Keap1, Kelch-like ECH-associated protein 1; GST, glutathione transferase; Nqo1, NAD(P)H:quinone oxidoreductase 1; HFD, high-fat diet; MDA, malondialdehyde; ND, normal diet; PCR, polymerase chain reaction; PGC, peroxisome proliferator-activated receptor γ coactivator; TBARS, thiobarbituric acid reactive substances; L-FABP, liver fatty acid-binding protein; Gstm6, Gst mu 6; SR-B1, scavenger-receptor class B, type 1; FAT, fatty acid translocase.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received December 21, 2007.
- Accepted February 14, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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