Regulation of hepatic lipogenesis by the transcription factor XBP1.
Dietary carbohydrates regulate hepatic lipogenesis by controlling the expression of critical enzymes in glycolytic and lipogenic pathways. We found that the transcription factor XBP1, a key regulator of the unfolded protein response, is required for the unrelated function of normal fatty acid synthesis in the liver. XBP1 protein expression in mice was elevated after feeding carbohydrates and corresponded with the induction of critical genes involved in fatty acid synthesis. Inducible, selective deletion of XBP1 in the liver resulted in marked hypocholesterolemia and hypotriglyceridemia, secondary to a decreased production of lipids from the liver. This phenotype was not accompanied by hepatic steatosis or compromise in protein secretory function. The identification of XBP1 as a regulator of lipogenesis has important implications for human dyslipidemias.
Lee
Ann-Hwee
AH
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. ahlee@hsph.harvard.edu
Scapa
Erez F
EF
Cohen
David E
DE
Glimcher
Laurie H
LH
D000818:Animals; D002784:Cholesterol / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D005227:Fatty Acids / Q000096:biosynthesis*; D005632:Fructose / Q000008:administration & dosage; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D017510:Protein Folding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D004040:Dietary Carbohydrates; D005227:Fatty Acids; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014280:Triglycerides; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D005632:Fructose; D002784:Cholesterol