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

Joseph L. Goldstein,Jian Yang,Michael S. Brown,Guosheng Liang,Robert E. Hammer,Jay D. Horton

doi:10.1074/jbc.m111421200

Joseph L. Goldstein, Jian Yang + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m111421200

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Abstract

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 of SREBP-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.

Highlights

¶ Pew Scholar in the Biomedical Sciences and recipient of an Established Investigator Grant from the American Heart Association and a Research Scholar Award from the American Digestive Health Foundation Industry
The current data demonstrate that basal levels of mRNAs encoding enzymes of fatty acid and triglyceride synthesis are reduced in livers of mice lacking SREBP-1c, but some of these mRNAs rise to nearly normal levels when fasted SREBP-1cϪ/Ϫ mice are refed a high carbohydrate diet that elevates plasma insulin and suppresses plasma glucagon
The data indicate that nuclear SREBPs are required for an increase in acetylCoA carboxylase (ACC) and fatty acid synthase (FAS) mRNAs in response to refeeding, they do not establish whether the SREBPs must rise in order to have this effect or whether they may remain constant, their presence being necessary to allow some other insulin-induced factor to act

Summary

EXPERIMENTAL PROCEDURES

Methods—Measurements of cholesterol and triglycerides in plasma and liver [14], preparation of nuclear extracts and membrane fractions from mouse liver [27], immunoblot analyses of mouse SREBP-1 and -2 [4], and RNase protection assays of SREBP-1a, -1c, and -2 mRNAs [2] were carried out as described in the indicated references. Primer sequences of genes not shown here have been described previously [16]

ABC transporters Other

Wild type

RESULTS

Insulin receptor

Wild type Fasted

DISCUSSION