Lipogenesis in liver is highest in the postprandial state; insulin activates SREBP-1c, which transcriptionally activates genes involved in FA synthesis, whereas glucose activates carbohydrate-responsive element-binding protein (ChREBP), which activates both glycolysis and FA synthesis. Whether SREBP-1c and ChREBP act independently of one another is unknown. Here, we characterized mice with liver-specific deletion of ChREBP (L-Chrebp−/− mice). Hepatic ChREBP deficiency resulted in reduced mRNA levels of glycolytic and lipogenic enzymes, particularly in response to sucrose refeeding following fasting, a dietary regimen that elicits maximal lipogenesis. mRNA and protein levels of SREBP-1c, a master transcriptional regulator of lipogenesis, were also reduced in L-Chrebp−/− livers. Adeno-associated virus-mediated restoration of nuclear SREBP-1c in L-Chrebp−/− mice normalized expression of a subset of lipogenic genes, while not affecting glycolytic genes. Conversely, ChREBP overexpression alone failed to support expression of lipogenic genes in the livers of mice lacking active SREBPs as a result of Scap deficiency. Together, these data show that SREBP-1c and ChREBP are both required for coordinated induction of glycolytic and lipogenic mRNAs. Whereas SREBP-1c mediates insulin’s induction of lipogenic genes, ChREBP mediates glucose’s induction of both glycolytic and lipogenic genes. These overlapping, but distinct, actions ensure that the liver synthesizes FAs only when insulin and carbohydrates are both present.

This article is available online at http://www.jlr.org endoplasmic reticulum (ER) to Golgi, where they are processed proteolytically to yield active nuclear forms. When cells are sterol-replete, Insig , an ER-resident membrane protein, binds Scap and retains the Scap-SREBP complex in the ER, thereby preventing the proteolytic activation of SREBPs ( 2, 3 ).In cells lacking Scap, SREBP transport to the Golgi is abolished, blocking SREBP proteolysis and leading to reduced rates of de novo cholesterol and fatty acid synthesis. As a result, Scap-defi cient cultured cells cannot grow without supplementation with exogenous cholesterol and fatty acids ( 4 ). The in vivo function of Scap has been explored most thoroughly in the liver, which is quantitatively the most important organ for cholesterol synthesis in most mammals ( 5 ). When Scap is ablated through gene knockout in rodent livers, nuclear SREBPs are not detectable, leading to reduced rates of hepatic cholesterol and fatty acid synthesis and reduced levels of cholesterol and triglycerides in the liver and plasma ( 6 ). Mice with defi ciency of Scap in the liver appear phenotypically normal and have grossly normal liver function. These mice are protected from development of fatty liver and carbohydrate-induced hypertriglyceridemia, suggesting that Scap inhibition may be a potential therapeutic strategy for the treatment of nonalcoholic fatty liver disease and hyperlipidemia ( 7 ).Determining the extrahepatic role of Scap is of interest both to elucidate the role of SREBP-mediated lipid homeostasis in extrahepatic tissues and to assess for toxicity arising from Scap inhibition in the context of the whole Grant HL-20948. M.R.M. is an Howard Hughes Medical Institute International Student Research Fellow. L.J.E. was supported by NIH Institutional Training Grant 2T32-DK-007745-16 and by NIH Grant 1K08DK102652-01. Manuscript received 31 March 2015 and in revised form 17 April 2015. Published, JLR Papers in Press, April 20, 2015 DOI 10.1194 Scap is required for sterol synthesis and crypt growth in intestinal mucosa Abbreviations: 4-OHT, 4-hydroxytamoxifen; ChgA, chromogranin A; CREB, cAMP response element binding protein; ER, endoplasmic reticulum; H&E, hematoxylin and eosin; HMGR, HMG-CoA reductase; IEC, intestinal epithelial cell; LGR5, leucine-rich repeat containing G protein-coupled receptor 5; M ␤ CD, methyl-␤ -cyclodextrin; NGS, normal goat serum; NPC1L1, Niemann-Pick C1-like 1 protein; PAS/AB, periodic acid-Schiff-Alcian Blue; QPCR, quantitative real-time RT-PCR; Scap, SREBP cleavage-activating protein; SREBP, sterol regulatory element-binding protein; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling .

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