2015/12/19 by Laurent Vergnes, Robert Chin, Robert G. Chin +6 · 25 citations
Medicine · Biochemistry, Genetics and Molecular Biology · #Cholesterol and Lipid Metabolism #Peroxisome Proliferator-Activated Receptors #Drug Transport and Resistance Mechanisms
paper · pdf · doi:10.1194/jlr.m064022
Cholesterol and fatty acid biosynthesis are regulated by the sterol regulatory element-binding proteins (SREBPs), encoded by Srebf1 and Srebf2. We generated mice that were either deficient or hypomorphic for SREBP-2. SREBP-2 deficiency generally caused death during embryonic development. Analyses of Srebf2−/− embryos revealed a requirement for SREBP-2 in limb development and expression of morphogenic genes. We encountered only one viable Srebf2−/− mouse, which displayed alopecia, attenuated growth, and reduced adipose tissue stores. Hypomorphic SREBP-2 mice (expressing low levels of SREBP-2) survived development, but the female mice exhibited reduced body weight and died between 8 and 12 weeks of age. Male hypomorphic mice were viable but had reduced cholesterol stores in the liver and lower expression of SREBP target genes. Reduced SREBP-2 expression affected SREBP-1 isoforms in a tissue-specific manner. In the liver, reduced SREBP-2 expression nearly abolished Srebf1c transcripts and reduced Srebf1a mRNA levels. In contrast, adipose tissue displayed normal expression of SREBP target genes, likely due to a compensatory increase in Srebf1a expression. Our results establish that SREBP-2 is critical for survival and limb patterning during development. Reduced expression of SREBP-2 from the hypomorphic allele leads to early death in females and reduced cholesterol content in the liver, but not in adipose tissue. Cholesterol and fatty acid biosynthesis are regulated by the sterol regulatory element-binding proteins (SREBPs), encoded by Srebf1 and Srebf2. We generated mice that were either deficient or hypomorphic for SREBP-2. SREBP-2 deficiency generally caused death during embryonic development. Analyses of Srebf2−/− embryos revealed a requirement for SREBP-2 in limb development and expression of morphogenic genes. We encountered only one viable Srebf2−/− mouse, which displayed alopecia, attenuated growth, and reduced adipose tissue stores. Hypomorphic SREBP-2 mice (expressing low levels of SREBP-2) survived development, but the female mice exhibited reduced body weight and died between 8 and 12 weeks of age. Male hypomorphic mice were viable but had reduced cholesterol stores in the liver and lower expression of SREBP target genes. Reduced SREBP-2 expression affected SREBP-1 isoforms in a tissue-specific manner. In the liver, reduced SREBP-2 expression nearly abolished Srebf1c transcripts and reduced Srebf1a mRNA levels. In contrast, adipose tissue displayed normal expression of SREBP target genes, likely due to a compensatory increase in Srebf1a expression. Our results establish that SREBP-2 is critical for survival and limb patterning during development. Reduced expression of SREBP-2 from the hypomorphic allele leads to early death in females and reduced cholesterol content in the liver, but not in adipose tissue. Cholesterol is a precursor for the biosynthesis of steroid hormones, bile acids, and vitamin D, and is a critical determinant of cell membrane permeability and fluidity (1Lingwood D. Simons K. Lipid rafts as a membrane-organizing principle.Science. 2010; 327: 46-50Crossref PubMed Scopus (3201) Google Scholar, 2Maxfield F.R. van Meer G. Cholesterol, the central lipid of mammalian cells.Curr. Opin. Cell Biol. 2010; 22: 422-429Crossref PubMed Scopus (246) Google Scholar). Cholesterol biosynthesis and homeostasis are regulated by the sterol regulatory element-binding protein (SREBP) transcription factor family. SREBPs are basic-helix-loop-helix-leucine zipper transcription factors, which are activated in response to low cellular sterol levels by a series of protein cleavage/transport events (3Horton J.D. Goldstein J.L. Brown M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.J. Clin. Invest. 2002; 109: 1125-1131Crossref PubMed Scopus (3757) Google Scholar, 4Jeon T-I. Osborne T.F. SREBPs: metabolic integrators in physiology and metabolism.Trends Endocrinol. Metab. 2012; 23: 65-72Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar, 5Ye J. DeBose-Boyd R.A. Regulation of cholesterol and fatty acid synthesis.Cold Spring Harb. Perspect. Biol. 2011; 3: a004754Crossref PubMed Scopus (179) Google Scholar). There are three SREBP isoforms, which originate from two genes. Srebf1 encodes SREBP-1a and SREBP-1c, which have distinct promoters and 5′ exons. Srebf2 encodes SREBP-2. SREBP-1c is the predominant isoform in metabolic tissues such as liver and adipose tissue, but has a relatively weak transcription-activation domain compared with the other SREBPs. There is overlap in the activities of the SREBP isoforms, but it is generally held that SREBP-1c primarily targets genes implicated in fatty acid synthesis, whereas SREBP-2 preferentially regulates genes involved in cholesterol synthesis (5Ye J. DeBose-Boyd R.A. Regulation of cholesterol and fatty acid synthesis.Cold Spring Harb. Perspect. Biol. 2011; 3: a004754Crossref PubMed Scopus (179) Google Scholar, 6Pai J.T. Guryev O. Brown M.S. Goldstein J.L. Differential stimulation of cholesterol and unsaturated fatty acid biosynthesis in cells expressing individual nuclear sterol regulatory element-binding proteins.J. Biol. Chem. 1998; 273: 26138-26148Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 7Horton J.D. Shah N.A. Warrington J.A. Anderson N.N. Park S.W. Brown M.S. Goldstein J.L. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes.Proc. Natl. Acad. Sci. USA. 2003; 100: 12027-12032Crossref PubMed Scopus (1072) Google Scholar, 8McPherson R. Gauthier A. Molecular regulation of SREBP function: the Insig-SCAP connection and isoform-specific modulation of lipid synthesis.Biochem. Cell Biol. 2004; 82: 201-211Crossref PubMed Scopus (101) Google Scholar). SREBP-1a is a potent activator of both triglyceride and cholesterol biosynthetic pathways, but is expressed at low levels in metabolic tissues, making the physiological role of the protein unclear (9Shimano H. Horton J.D. Shimomura I. Hammer R.E. Brown M.S. Goldstein J.L. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells.J. Clin. Invest. 1997; 99: 846-854Crossref PubMed Scopus (683) Google Scholar). SREBP-1c, itself, is regulated by SREBPs, indicating a high degree of cross-talk among SREBP proteins, making it difficult to assign distinct physiological functions to individual SREBP proteins. SREBP activity is regulated by the nutritional status of the cell (10Goldstein J.L. DeBose-Boyd R.A. Brown M.S. Protein sensors for membrane sterols.Cell. 2006; 124: 35-46Abstract Full Text Full Text PDF PubMed Scopus (1230) Google Scholar, 11Goldstein J.L. Brown M.S. A century of cholesterol and coronaries: from plaques to genes to statins.Cell. 2015; 161: 161-172Abstract Full Text Full Text PDF PubMed Scopus (633) Google Scholar). When cellular sterol concentrations are high, SREBP precursors are bound to SREBP cleavage-activating protein (SCAP) in the endoplasmic reticulum membrane. SCAP, in turn, interacts with insulin-induced proteins (Insigs), which serve to retain the SCAP-SREBP complex within the endoplasmic reticulum membrane. When sterol concentrations are low, SCAP-bound SREBPs are translocated to the Golgi where they undergo a two-step cleavage process (by S1P and S2P proteases), thereby releasing the N-terminal active domain (nuclear SREBP). Studies with genetically modified mice have provided insight into the physiological roles of the three SREBP isoforms [reviewed in (3Horton J.D. Goldstein J.L. Brown M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.J. Clin. Invest. 2002; 109: 1125-1131Crossref PubMed Scopus (3757) Google Scholar, 5Ye J. DeBose-Boyd R.A. Regulation of cholesterol and fatty acid synthesis.Cold Spring Harb. Perspect. Biol. 2011; 3: a004754Crossref PubMed Scopus (179) Google Scholar)]. The characterization of transgenic mice with expression of constitutively active nuclear forms of SREBP-1a, -1c, or -2 led to the identification of preferential target genes for SREBP-1 (lipogenesis genes) and SREBP-2 (cholesterol synthetic genes) (9Shimano H. Horton J.D. Shimomura I. Hammer R.E. Brown M.S. Goldstein J.L. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells.J. Clin. Invest. 1997; 99: 846-854Crossref PubMed Scopus (683) Google Scholar, 12Horton J.D. Shimomura I. Brown M.S. Hammer R.E. Goldstein J.L. Shimano H. Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2.J. Clin. Invest. 1998; 101: 2331-2339Crossref PubMed Google Scholar, 13Shimano H. Horton J.D. Hammer R.E. Shimomura I. Brown M.S. Goldstein J.L. Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a.J. Clin. Invest. 1996; 98: 1575-1584Crossref PubMed Scopus (698) Google Scholar). However, the physiological roles of the SREBP proteins cannot be fully delineated with constitutively active transgenes that lack the capacity to be regulated by sterols. Studies with gene knockout models have largely confirmed the gene targets for SREBP-1 and have provided additional insights into the physiological roles of this protein. Because of the critical functions of the SREBP pathway, SREBP-1 deficiency is lethal in utero in 50–85% of mice (14Shimano H. Shimomura I. Hammer R.E. Herz J. Goldstein J.L. Brown M.S. Horton J.D. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene.J. Clin. Invest. 1997; 100: 2115-2124Crossref PubMed Scopus (353) Google Scholar). Although no analysis of SREBP-2-deficient mice has been published, Shimano et al. (14Shimano H. Shimomura I. Hammer R.E. Herz J. Goldstein J.L. Brown M.S. Horton J.D. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene.J. Clin. Invest. 1997; 100: 2115-2124Crossref PubMed Scopus (353) Google Scholar) did comment that SREBP-2 deficiency is lethal during embryogenesis. Also, deficiency in S1P, which is required for activation of all SREBP isoforms, is lethal in utero (15Yang J. Goldstein J.L. Hammer R.E. Moon Y.A. Brown M.S. Horton J.D. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene.Proc. Natl. Acad. Sci. USA. 2001; 98: 13607-13612Crossref PubMed Scopus (188) Google Scholar). SCAP and S1P function has been examined with conditional gene knockouts in liver, which revealed marked (70–80%) reductions in hepatic cholesterol and fatty acid levels (15Yang J. Goldstein J.L. Hammer R.E. Moon Y.A. Brown M.S. Horton J.D. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene.Proc. Natl. Acad. Sci. USA. 2001; 98: 13607-13612Crossref PubMed Scopus (188) Google Scholar, 16Matsuda M. Korn B.S. Hammer R.E. Moon Y.A. Komuro R. Horton J.D. Goldstein J.L. Brown M.S. Shimomura I. SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation.Genes Dev. 2001; 15: 1206-1216Crossref PubMed Scopus (265) Google Scholar). Although the SREBP-1-, S1P-, and SCAP-deficient mice have revealed the importance of the SREBP pathway during embryogenesis, the role of each protein during development has not been studied in detail. It is intuitive that lipid homeostasis should be critical for normal development, because upregulation of cholesterol and phospholipid synthesis is required to satisfy the demand for membrane biogenesis during periods of rapid cell proliferation. Also, it is that sterol synthesis results in in and of to a of cholesterol Lipid 2002; Full Text Full Text PDF PubMed Google Scholar, Molecular limb with cholesterol deficiency during of 2003; PubMed Scopus Google Scholar, J.A. Cholesterol of proteins in 1996; PubMed Scopus Google Scholar, M. and PubMed Scopus Google Scholar). However, the activities of SREBP-1 and SREBP-2 that for development have not been In the to the physiological role of SREBP-2 during embryonic development and in the liver and adipose tissue of of were a allele for Srebf2. allele it to both SREBP-2-deficient mice and hypomorphic SREBP-2 embryonic cells a in Srebf2 were from M. et a to all gene cell in 2006; PubMed Scopus Google Scholar, D. M. R.E. A. et a of in embryonic 2003; PubMed Scopus Google Scholar). of the into Srebf2 by direct of by 5′ rapid of Male mice from were with females to mice the Srebf2 The of the within of the Srebf2 gene by were by of with for the Srebf2 allele and for the allele the Srebf2 hypomorphic mice were with transgenic mice A transgenic in 2002; PubMed Scopus Google Scholar). The the in the by a in the of the generated from the allele to The by were in a 12 and a were were from the of at and tissues were in and as R. K. deficiency causes and to Lipid 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). and embryos were for as R. R.A. M. K. et lipid biosynthetic gene required for in Lipid 2006; Full Text Full Text PDF PubMed Scopus Google Scholar) with were in and were with and in for and in at were in for three in and with and as in as The were of role in activity during 2004; PubMed Scopus Google Scholar, H. in and requirement for in the development of PubMed Scopus Google Scholar, 1998; 22: PubMed Scopus Google Scholar). embryonic were from embryos were at in with and were by were the cells were with and The results were with two and cell from tissues and by with synthesis, and were as R. K. deficiency causes and to Lipid 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). expression to and in this are in expression by a from from and to were in and in A tissue with a cell and the at for at The at for at The in A to the The in of were for Protein with SREBP-2 T-I. J. Osborne T.F. of SREBP-2 in hepatic a role in Metab. 2011; Full Text Full Text PDF PubMed Scopus Google by and with tissue lipid were as R. K. deficiency causes and to Lipid 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). proteins were for between were by the at models with or reduced a allele in of Srebf2. The from this allele of Srebf2 to a of a and a The protein only the acids of it of the SREBP-2 the and mice Srebf2−/− mice died in from a is in with Shimano et al. (14Shimano H. Shimomura I. Hammer R.E. Herz J. Goldstein J.L. Brown M.S. Horton J.D. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene.J. Clin. Invest. 1997; 100: 2115-2124Crossref PubMed Scopus (353) Google that Srebf2 knockout mice during the embryos were not SREBP-2 expression during embryogenesis, examined embryos for which is by the Srebf2 regulatory levels of Srebf2 expression were embryonic the in the and in all of the and in the and the of limb in nearly all tissues, with and the high levels of the of SREBP-2 deficiency during development, embryos at Srebf2−/− embryos died between and the Srebf2−/− embryos a limb with and and The within the and to embryonic The in Srebf2−/− embryos that SREBP-2 is required for limb There are two in the early limb the of activity and the J. limb Cell Dev. Biol. 2001; PubMed Scopus Google Scholar, R. limb from to patterning Spring Harb. Perspect. Biol. PubMed Scopus Google Scholar). are the of that of the and are a regulatory and The J. A. 2003; PubMed Scopus Google Scholar, insight into the Opin. Dev. 2006; PubMed Scopus Google Scholar, A. R. by the in limb PubMed Scopus Google Scholar, of limb PubMed Scopus Google Scholar, R. A expression during limb PubMed Scopus Google Scholar). such as and proteins are critical for the from the and for in the R. limb from to patterning Spring Harb. Perspect. Biol. PubMed Scopus Google Scholar). with the between the and are for limb and The J. A. 2003; PubMed Scopus Google Scholar). We the expression of and patterning genes with in We embryos at at which the are but limb in SREBP-2-deficient embryos are not expression in the and expressed at levels in Srebf2−/− compared with embryos of the reduced in and of Srebf2−/− embryos with development, activation of by leads to the of the and of the transcription which target genes such as The Srebf2−/− embryos exhibited in but not of genes in the Although levels of mRNA were not in Srebf2−/− the target expressed at reduced levels in Srebf2−/− limb but increased expression in the and expression and expression in Srebf2−/− results that lack of SREBP-2 in the leads to regulation of genes involved in limb the role of SREBP-2 and cholesterol homeostasis during embryonic development, generated from and embryos and expression of genes. of genes for the in revealed of Srebf2 deficiency the expression of Srebf2−/− caused marked reductions in the expression of and and a increase in expression The of levels in from the normal levels of expression in Srebf2−/− embryos that compensatory in gene expression in of not affected by Srebf2 deficiency SREBP-2 in the regulation of gene either or We the of cholesterol deprivation and gene expression. were with a of cholesterol cellular cholesterol and cholesterol in the deprivation in had as Srebf2 gene expression whereas and were results that SREBP-2 and cellular cholesterol have a role in limb genes. the role of SREBP-2 cholesterol homeostasis in the liver during embryonic development, embryos at and expression of and target genes in the from the of the body and triglyceride levels were in and Srebf2−/− embryos Srebf2 mRNA levels in liver were nearly and target genes involved in cholesterol synthesis SREBP protein and cellular cholesterol were reduced reduced by were Srebf1a and Srebf1c levels with a regulatory between SREBP-2 and SREBP-1c R. J. M. regulation of sterol regulatory element-binding protein-2.J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Shimano H. H. K. et analysis of the sterol regulatory element-binding gene.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We reduced transcripts for fatty acid synthesis genes embryos displayed reduced expression of both SREBP-1c and SREBP-2 target genes. We one viable Srebf2−/− from a of from of the SREBP-2-deficient and less than Srebf2 deficiency confirmed by of SREBP-2 protein in the liver The of the liver to that of to body weight The Srebf2−/− had reduced with nearly adipose tissue and reduced of tissue from the revealed with reduced lipid the of and tissue in but adipose in the Srebf2−/− limb were encountered in Srebf2−/− the of the Srebf2−/− normal The Srebf2−/− provided to of SREBP-2 deficiency liver and adipose tissue and gene expression levels. The of Srebf2 deficiency in liver in Srebf2−/− Although analysis not due to of only a Srebf2−/− mouse, hepatic cholesterol levels in the Srebf2−/− were reduced by and levels were reduced by levels for Srebf1a and Srebf1c in the liver were as were the transcripts for SREBP target genes In cholesterol levels were reduced by compared with but levels to were In to the liver of the Srebf2−/− mouse, SREBP target genes in were expressed at levels to in mice Srebf1a mRNA levels in were whereas Srebf1c mRNA levels were In the expression levels for and were to in in the adipose tissue of the Srebf2−/− mouse, levels of Srebf1a expression have for the of SREBP-2. were to a viable Srebf2−/− mouse, embryonic from SREBP-2 function in this to the in the with the of of normal mRNA and mice with a hypomorphic Srebf2 allele of and mice generated of which with were for the hypomorphic and SREBP-2 protein levels in the mice were lower than in mice mice normal during the but the females had reduced body weight at weeks of and of died between 8 and 12 weeks of Male mice exhibited normal body weight and survived the at 12 weeks of age. with mice had lower tissue and lower liver to body We that steroid synthesis to in female However, of levels did not a likely of the death in and levels were normal in Male mice had levels of and in the steroid in a We studied mice to of reduced SREBP-2 expression cholesterol 12 weeks of had reduced cholesterol levels in the liver, but not in adipose tissue levels were normal Reduced SREBP-2 expression led to lower expression of cholesterol biosynthetic and genes in the liver but not in adipose tissue mice had reduced Srebf1 gene with lower Srebf1c mRNA levels in liver and lower Srebf1c levels in adipose tissue. Srebf1a levels were in both tissues The adipose tissue of mice displayed a increase in transcripts for the that the gene for within of the Srebf2 allele leads to mRNA expression. levels and mRNA levels for target genes were in livers of and mice mRNA levels were in the hypomorphic but because and other target genes were expressed at this is a of The gene expression in tissues of Srebf2−/− and mice have been by compensatory the of SREBP-2 deficiency gene gene expression and sterol regulation of gene expression in Srebf2−/− with in the two of each cholesterol biosynthetic genes and were expressed at lower levels in the Srebf2−/− the gene expression in the liver of mice SREBP-2 deficiency in led to nearly Srebf1c mRNA but to increased levels of Srebf1a transcripts SREBP-2 deficiency the regulation of gene expression in response to sterol with a to SREBP target genes, with the of Srebf1a the two at the of each SREBP-2 is required for expression of but not and is for sterol regulation of SREBP target genes. It has been that SREBP-2 is a of lipid SREBP-1 and SREBP-2 preferentially target genes involved in fatty acid synthesis and cholesterol J.D. Shah N.A. Warrington J.A. Anderson N.N. Park S.W. Brown M.S. Goldstein J.L. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes.Proc. Natl. Acad. Sci. USA. 2003; 100: 12027-12032Crossref PubMed Scopus (1072) Google Scholar). However, the activities of the two transcription making it to physiological of SREBP-1 deficiency in the (14Shimano H. Shimomura I. Hammer R.E. Herz J. Goldstein J.L. Brown M.S. Horton J.D. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene.J. Clin. Invest. 1997; 100: 2115-2124Crossref PubMed Scopus (353) Google but the of SREBP-2 deficiency not a of two Srebf2 to the roles of SREBP-2 in development and in We a role for SREBP-2 in survival and in limb patterning the We a role for SREBP-2 in hepatic cholesterol content and in Srebf1 gene in to SREBP-2 target genes. SREBP-2 deficiency is with normal embryonic Srebf2−/− embryos died by likely no one has encountered or studied a with complete SREBP-2 In the mouse, a Srebf2 with and R. R. A in Srebf2 leads to and in the 2011; 22: PubMed Scopus Google but the of the acid SREBP-2 activity is but to The of death in Srebf2−/− embryos is that Srebf2 expression is expressed and have been by the of SREBP-2. A of Srebf2−/− embryos Srebf2 expression is in the limb of embryos in the to undergo during The of in Srebf2−/− embryos confirmed a requirement for SREBP-2 in this is in with that in the limb is between cholesterol biosynthetic gene activity and the process that the D. R. J. expression of genes is to distinct and with in 2003; PubMed Scopus Google Scholar). expression in Srebf2−/− embryos revealed in that limb of the of Srebf2−/− embryos exhibited increased but reduced expression of of the pathway that both and both R. roles of in J. 2004; PubMed Scopus Google it is to that SREBP-2 regulation of cholesterol levels in the a role in the of this pathway, but additional is Our results in the mice that low levels of SREBP-2 expression are for survival during embryogenesis. mice are at a the of but the females exhibited and during the of analysis of steroid not in the in the survival of and Studies of mice revealed a complex between Srebf2 expression and the regulation of that of SREBP-1 leads to increased hepatic SREBP-2 and protein increased expression of cholesterol biosynthetic genes, and a increase in hepatic cholesterol content (14Shimano H. Shimomura I. Hammer R.E. Herz J. Goldstein J.L. Brown M.S. Horton J.D. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene.J. Clin. Invest. 1997; 100: 2115-2124Crossref PubMed Scopus (353) Google Scholar). We that reduced SREBP-2 expression in mice in tissue-specific in Srebf1 expression. In the liver, the mice had nearly levels of Srebf1c transcripts and in Srebf1a The low levels of SREBPs in mice were by lower stores of cholesterol in the In contrast, the cholesterol content of adipose tissue and embryonic a in Srebf1c because of increased Srebf1a expression levels. of Srebf2 encodes a which to be generated as a of mRNA transcription of the Srebf2 gene A. SREBP-2 to of sterol Natl. Acad. Sci. USA. 2010; PubMed Scopus Google Scholar, A. to the regulation of cholesterol 2010; PubMed Scopus Google Scholar, R.E. and the SREBP genes to cholesterol 2010; PubMed Scopus Google Scholar, H. The nuclear the of from Biol. 2015; PubMed Scopus Google Scholar). targets transcripts from genes involved in cellular cholesterol such as and and has been as R.E. van et of in mice cholesterol and of Clin. Invest. 2011; PubMed Scopus Google Scholar, O. M. M. K. M. et deficiency the of in 2012; PubMed Scopus Google Scholar). It is that the expression of Srebf2 and a to cellular cholesterol homeostasis by cholesterol synthesis sterol Because is within the Srebf2 it that levels be reduced in However, the expression of and target genes were not in the liver, that the Srebf2 allele did not expression. the of mice did not of which hepatic and are to increased body weight and O. M. M. et regulates sterol regulatory element-binding protein expression in PubMed Scopus Google Scholar). It is that is by or that are compensatory in mice that serve to levels for target genes. a for of hypomorphic from has been a to for gene function in mice M. et a to all gene cell in 2006; PubMed Scopus Google Scholar, D. M. R.E. A. et a of in embryonic 2003; PubMed Scopus Google Scholar). of which is it is the that a gene in mice results in during embryonic development. In the of tissue-specific knockout mice to gene In the that the of a hypomorphic allele from the a for gene We to the in the which a low of Srebf2 transcripts and led to reduced SREBP-2 levels the this is not to a hypomorphic it have been to a cell to mice that low of SREBP-2 in a tissue. The for in with protein factor insulin-induced protein embryonic SREBP cleavage-activating protein sterol regulatory element-binding protein adipose tissue of activity