Diminished Hepatic Response to Fasting/Refeeding and Liver X Receptor Agonists in Mice with Selective Deficiency of Sterol Regulatory Element-binding Protein-1c*

By G. Liang, Jian Yang, Jay D. Horton, R. Hammer, J. Goldstein, Michael S. Brown. Journal of Biological Chemistry, 2002

663 citations recorded by the source corpus.

Two treatments, fasting/refeeding and administration of liver X receptor (LXR) agonists, elevate the mRNA for sterol regulatory element-binding protein-1c (SREBP-1c) and enhance lipid synthesis in liver. These treatments do not affect the mRNA for SREBP-1a, an alternative transcript from the same gene. Through homologous recombination, we eliminated the exon encoding SREBP-1c from the mouse genome, leaving the SREBP-1a transcript intact. On a normal diet, livers ofSREBP-1c −/− mice manifested reductions in multiple mRNAs encoding enzymes of fatty acid and triglyceride synthesis, including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). In contrast, SREBP-1c −/−livers showed a compensatory increase in hepatic SREBP-2 mRNA, accompanied by increased mRNA levels for cholesterol biosynthetic enzymes. In fasted/refed animals, ACC and FAS mRNAs rose, but not to the same extent as in wild-type livers. The refeeding-induced increase in SREBP-1c −/− mice was greater than in mice lacking SREBP cleavage-activating protein (SCAP), in which all nuclear SREBPs are absent. Thus, SREBP-2 and/or SREBP-1a can substitute partially for SREBP-1c in permitting an insulin-mediated increase in ACC and FAS mRNAs. In contrast, mRNAs for several other lipogenic enzymes (glucose-6-phosphate dehydrogenase, malic enzyme, glycerol-3-phosphate acyltransferase, and stearoyl-CoA desaturase-1) showed a complete failure of the normal inductive response to refeeding, indicating specific reliance on SREBP-1c. Moreover, these mRNAs, as well as multiple other lipogenic mRNAs, showed a markedly blunted response to the LXR agonist T090137, indicating an essential role of SREBP-1c in the LXR response.

Subfields: Molecular Biology, Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/9453421bf6d3aa803a9b638f2cfd265e8e767dfd

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Citations in the corpus

Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. (2002, positive): “lated and pooled for real-time PCR using oligonucleotides as described (18, 39).”
Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP‐1c (2010, background): “As mentioned before, SREBP-1c activity alone does not appear to fully account for the stimulation of lipogenic gene expression in response to carbohydrate because SREBP-1c gene deletion in mice only results in a 50% reduction in fatty acid synthesis [52].”
Enzymes of triacylglycerol synthesis and their regulation. (2004, background): “When fasted animals are refed, the hepatic expression of lipogenic enzymes increases in normal, but not in SREBP-1c knockout mice [207].”
Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. (2004, background): “Data on the SREBP-1c (55), SCAP (56), and S1P (57) knockout mice further prove that the SREBP pathway is important for TG synthesis in the liver and the determination of serum TG levels.”
From mice to men: insights into the insulin resistance syndromes. (2006, background): “However, mice lacking SREBP-1c have a 50% decrease in serum triglycerides and a 10% decrease in serum cholesterol (118).”