Overactivation of Intestinal SREBP2 in Mice Increases Serum Cholesterol

Ma, Ke; Malhotra, P.K.; Soni, Vinay; Hedroug, Omar; Annaba, Fadi; Dudeja, Amish K.; Shen, Le; Turner, Jerrold R.; Khramtsova, Ekaterina A.; Saksena, Seema; Dudeja, Pradeep K.; Gill, Ravinder K.; Alrefai, Waddah A.

doi:10.1371/journal.pone.0084221

Cited by 31 publications

(28 citation statements)

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“…We observed signifi cant increases in the amount of intestinal nuclear SREBPs and cholesterol synthesis, such that synthesis in the intestine exceeded that in liver on an organ-by-organ basis ( 14 ). Similar results were found when truncated SREBP-2 was expressed in intestinal epithelia ( 15 ). These results indicated that Insig proteins mediate feedback inhibition of cholesterol synthesis in the intestine and suggested that Scap, the binding partner for Insig, also likely plays a role in SREBP processing in the intestine.…”

Section: Quantitative Real-time Rt-pcrsupporting

confidence: 83%

Scap is required for sterol synthesis and crypt growth in intestinal mucosa

McFarlane

Cantoria

Linden

et al. 2015

Journal of Lipid Research

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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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Section: Quantitative Real-time Rt-pcrsupporting

confidence: 83%

Scap is required for sterol synthesis and crypt growth in intestinal mucosa

McFarlane

Cantoria

Linden

et al. 2015

Journal of Lipid Research

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“…SREBP-1 governs fatty acid and triacylglyceride metabolism ( Guo et al, 2014 ; Bitter et al, 2015 ). In contrast, SREBP-2 is deeply involved in the regulation of cholesterol metabolism ( Ma et al, 2014 ) Reflecting such differences in biological function, the transcript for SREBP-1, which is most abundant in the liver and adrenal gland, has a shorter acidic activation domain, and the protein acts selectively to increase the mRNAs for enzymes involved in fatty acids synthesis ( Soyal et al, 2015 ). In contrast, the ubiquitously expressed SREBP-2 transcript has a long activation domain.…”

Section: Discussionmentioning

confidence: 99%

Sex-Related Differences of Lipid Metabolism Induced by Triptolide: The Possible Role of the LXRα/SREBP-1 Signaling Pathway

Jiang

Huang

et al. 2016

Front. Pharmacol.

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Triptolide, a diterpenoid isolated from the plant Tripterygium wilfordii Hook. f., exerts a unique bioactive spectrum of anti-inflammatory and anticancer activities. However, triptolide’s clinical applications are limited due to its severe toxicities. Fatty liver toxicity occurs in response to triptolide, and this toxic response significantly differs between males and females. This report investigated the pathogenesis underlying the sex-related differences in the dyslipidosis induced by triptolide in rats. Wistar rats were administered 0, 150, 300, or 450 μg triptolide/kg/day by gavage for 28 days. Ultrastructural examination revealed that more lipid droplets were present in female triptolide-treated rats than in male triptolide-treated rats. Furthermore, liver triglyceride, total bile acid and free fatty acid levels were significantly increased in female rats in the 300 and 450 μg/kg dose groups. The expression of liver X receptor α (LXRα) and its target genes, cholesterol 7α-hydroxylase (CYP7A1) and Sterol regulatory element-binding transcription factor 1(SREBP-1), increased following triptolide treatment in both male and female rats; however, the female rats were more sensitive to triptolide than the male rats. In addition, the expression of acetyl-CoA carboxylase 1(ACC1), a target gene of SREBP-1, increased in the female rats treated with 450 μg triptolide/kg/day, and ACC1 expression contributed to the sex-related differences in the triptolide-induced dysfunction of lipid metabolism. Our results demonstrate that the sex-related differences in LXR/SREBP-1-mediated regulation of gene expression in rats are responsible for the sex-related differences in lipid metabolism induced by triptolide, which likely underlie the sex-related differences in triptolide hepatotoxicity. This study will be important for predicting sex-related effects on the pharmacokinetics and toxicity of triptolide and for improving its safety.

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“…The underpinning reason for the discrepancy is not known, but immunofluorescence analysis for VSVG-LPA 2 expression showed that the expression levels of TG LPA 2 is about two-fold greater in the small intestine. Villin promoter activity and its expression are greater in the small intestine than in colon [ 26 , 27 ]. LPA is known to regulate actin cytoskeletal dynamics, which is closely associated with cell division [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Transgenic Expression of Human Lysophosphatidic Acid Receptor LPA2 in Mouse Intestinal Epithelial Cells Induces Intestinal Dysplasia

Yoshida

Yun

2016

PLoS ONE

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Lysophosphatidic acid (LPA) acts on LPA2 receptor to mediate multiple pathological effects that are associated with tumorigenesis. The absence of LPA2 attenuates tumor progression in rodent models of colorectal cancer, but whether overexpression of LPA2 alone can lead to malignant transformation in the intestinal tract has not been studied. In this study, we expressed human LPA2 in intestinal epithelial cells (IECs) under control of the villin promoter. Less than 4% of F1-generation mice had germline transmission of transgenic (TG) human LPA2; as such only 3 F1 mice out of 72 genotyped had TG expression. These TG mice appeared anemic with hematochezia and died shortly after birth. TG mice were smaller in size compared with the wild type mouse of the same age and sex. Morphological analysis showed that TG LPA2 colon had hyper-proliferation of IECs resulting in increased colonic crypt depth. Surprisingly, TG small intestine had villus blunting and decreased IEC proliferation and dysplasia. In both intestine and colon, TG expression of LPA2 compromised the terminal epithelial differentiation, consistent with epithelial dysplasia. Furthermore, we showed that epithelial dysplasia was observed in founder mouse intestine, correlating LPA2 overexpression with epithelial dysplasia. The current study demonstrates that overexpression of LPA2 alone can lead to intestinal dysplasia.

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Overactivation of Intestinal SREBP2 in Mice Increases Serum Cholesterol

Cited by 31 publications

References 31 publications

Scap is required for sterol synthesis and crypt growth in intestinal mucosa

Scap is required for sterol synthesis and crypt growth in intestinal mucosa

Sex-Related Differences of Lipid Metabolism Induced by Triptolide: The Possible Role of the LXRα/SREBP-1 Signaling Pathway

Transgenic Expression of Human Lysophosphatidic Acid Receptor LPA2 in Mouse Intestinal Epithelial Cells Induces Intestinal Dysplasia

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