Liver-specific expression of transcriptionally active SREBP-1c is associated with fatty liver and increased visceral fat mass

Knebel, Birgit; Haas, Jutta; Hartwig, Sonja; Jacob, Sylvia; Köllmer, Cornelia; Nitzgen, Ulrike; Muller–Wieland, Dirk; Kotzka, Jorg

doi:10.1371/journal.pone.0031812

Cited by 162Liver Disease Diagnosis and TreatmentLipid metabolism and biosynthesisCancer, Lipids, and Metabolism

Liver-specific expression of transcriptionally active SREBP-1c is associated with fatty liver and increased visceral fat mass

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Knebel, Birgit, Haas, Jutta, Hartwig, Sonja, Jacob, Sylvia, Köllmer, Cornelia, Nitzgen, Ulrike, Muller–Wieland, Dirk, Kotzka, Jorg·2012·PLoS ONE

DOI 10.1371/journal.pone.0031812PMC PMC3283692

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Abstract

The pathogenesis of fatty liver is not understood in detail, but lipid overflow as well as de novo lipogenesis (DNL) seem to be the key points of hepatocyte accumulation of lipids. One key transcription factor in DNL is sterol regulatory element-binding protein (SREBP)-1c. We generated mice with liver-specific over-expression of mature human SREBP-1c under control of the albumin promoter and a liver-specific enhancer (alb-SREBP-1c) to analyze systemic perturbations caused by this distinct alteration. SREBP-1c targets specific genes and causes key enzymes in DNL and lipid metabolism to be up-regulated. The alb-SREBP-1c mice developed hepatic lipid accumulation featuring a fatty liver by the age of 24 weeks under normocaloric nutrition. On a molecular level, clinical parameters and lipid-profiles varied according to the fatty liver phenotype. The desaturation index was increased compared to wild type mice. In liver, fatty acids (FA) were increased by 50% (p<0.01) and lipid composition was shifted to mono unsaturated FA, whereas lipid profile in adipose tissue or serum was not altered. Serum analyses revealed a ∼2-fold (p<0.01) increase in triglycerides and free fatty acids, and a ∼3-fold (p<0.01) increase in insulin levels, indicating insulin resistance; however, no significant cytokine profile alterations have been determined. Interestingly and unexpectedly, mice also developed adipositas with considerably increased visceral adipose tissue, although calorie intake was not different compared to control mice. In conclusion, the alb-SREBP-1c mouse model allowed the elucidation of the systemic impact of SREBP-1c as a central regulator of lipid metabolism in vivo and also demonstrated that the liver is a more active player in metabolic diseases such as visceral obesity and insulin resistance.

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In experimental models of obesity, metabolic defects involving substrate partitioning and energy expenditure may manifest without (or before) increased food intake.
“In experimental models of obesity, metabolic defects involving substrate partitioning and energy expenditure may manifest without (or before) increased food intake, demonstrating the conceptual plausibility of this fundamental feature of the CIM (60, 112–114).”
From The carbohydrate-insulin model: A physiological perspective on the obesity pandemic (2021) · cites this paper as [114]

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“Total RNA extraction, Real time (RT) PCR analyses (Assay on Demand, 26Universal PCR Mastermix, ABI Prism 7000 Sequence Detection System Applied Biosystems, Darmstadt, Germany) and specific detection of endogenous mouse SREBP-1a and SREBP-1c isoforms were performed with mSREBP-1aFP 59GAGGCGGCTCTGGAACAGA39 or mSREBP-1cF…”
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Phosphorylation of sterol regulatory element-binding protein (SREBP)-1a links growth hormone action to lipid metabolism in hepatocytes
Kotzka, J., Knebel, B., Avci, H., Jacob, S., Nitzgen, U., Jockenhövel, F., Heeren, J., Haas, J., & Müller‐Wieland, D. (2010) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2010.08.046 · Cited by 38 · see citing works
Self-citation
Environmental and Genetic Determinants of Fatty Liver in Humans
Kantartzis, K., Schick, F., Häring, H., & Stefan, N. (2010) · Digestive Diseases · doi:10.1159/000282082 · Cited by 32 · see citing works
Opening Chromatin
Lomvardas, S., & Thanos, D. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00463-x · Cited by 29 · see citing works
A Sweet Path to Insulin Resistance Through PGC-1β
Hernandez, C., & Lin, J. D. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.02.001 · Cited by 10 · see citing works
Expression of serum albumin and of alphafetoprotein in murine normal and neoplastic primitive embryonic structures
Trojan, J., Naval, X., Johnson, T. R., Lafarge‐Frayssinet, C., Hajeri‐Germond, M., Farges, O., Pan, Y., Uriel, J., Abramasky, O., Ilan, J., et al. (1995) · Molecular Reproduction and Development · doi:10.1002/mrd.1080420402 · Cited by 7 · see citing works

Flagged first, then by citations

Sorted by citations

Non-alcoholic fatty liver disease and obesity: Biochemical, metabolic and clinical presentations
Milić, S. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i28.9330 · Cited by 595 · see citing works
De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose
Sanders, F., & Griffin, J. L. (2015) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12178 · Cited by 543 · see citing works
“The role of SREBP1c in the pathogenesis of NAFLD is further supported by mouse studies where the transcriptionally active form of SREBP1c is expressed in a liver-specific manner and leads to a consequent accumulation of hepatic lipid droplets (Knebel et al., 2012).”
Background
The brown fat–enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis
Wang, G.-X., Zhao, X.-Y., Meng, Z., Kern, M., Dietrich, A., Chen, Z., Cozacov, Z., Zhou, D., Okunade, A. L., Su, X., et al. (2014) · Nature Medicine · doi:10.1038/nm.3713 · Cited by 508 · see citing works
Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues
Song, Z., Xiaoli, A. M., & Yang, F. (2018) · Nutrients · doi:10.3390/nu10101383 · Cited by 437 · see citing works
“For example, pathological increase of SREBP-1c or genetic overexpression of SREBP-1c in the liver causes fatty liver [55,56].”
Background
Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways
Badmus, O. O., Hillhouse, S. A., Anderson, C. D., Hinds, T. D., & Stec, D. E. (2022) · Clinical Science · doi:10.1042/cs20220572 · Cited by 372 · see citing works
“Hepatocyte-specific overexpression of SREBP-1c results in the upregulation of key enzymes in de novo lipogenesis resulting in hepatic lipid accumulation [67].”
Background
The carbohydrate-insulin model: A physiological perspective on the obesity pandemic
Ludwig, D. S., Aronne, L. J., Astrup, A., de Cabo, R., Cantley, L. C., Friedman, M. I., Heymsfield, S. B., Johnson, J. D., King, J. C., Krauss, R. M., et al. (2021) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqab270 · Cited by 292 · see citing works
De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health
Eissing, L., Scherer, T., Tödter, K., Knippschild, U., Greve, J. W. M., Buurman, W. A., Pinnschmidt, H. O., Rensen, S. S., Wolf, A. M., Bartelt, A., et al. (2013) · Nature Communications · doi:10.1038/ncomms2537 · Cited by 302 · see citing works
Free radical biology for medicine: learning from nonalcoholic fatty liver disease
Serviddio, G., Bellanti, F., & Vendemiale, G. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.08.174 · Cited by 269 · see citing works
“Liver-specific expression of transcriptionally active SREBP-1c is associated with hepatic steatosis [151].”
Background
Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes
Yung, J. H. M., & Giacca, A. (2020) · Cells · doi:10.3390/cells9030706 · Cited by 274 · see citing works
“Activation of SREBP-1c, a transcription factor that enhances de novo lipogenesis, causes further lipid accumulation [97].”
Background
MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice
Horie, T., Nishino, T., Baba, O., Kuwabara, Y., Nakao, T., Nishiga, M., Usami, S., Izuhara, M., Sowa, N., Yahagi, N., et al. (2013) · Nature Communications · doi:10.1038/ncomms3883 · Cited by 230 · see citing works
The Interplay between Insulin Resistance, Inflammation, Oxidative Stress, Base Excision Repair and Metabolic Syndrome in Nonalcoholic Fatty Liver Disease
Ziółkowska, S., Binienda, A., Jabłkowski, M., Szemraj, J., & Czarny, P. L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011128 · Cited by 209 · see citing works
“In vivo studies indicate that SREBP1c knockout mice have decreased expression of lipogenic enzymes, whereas transgenic mice overexpressing SREBP1c have higher hepatic TG levels and insulin levels, indicating IR [38,39].”
Background
Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia
Morrow, M. R., Batchuluun, B., Wu, J., Ahmadi, E., Leroux, J. M., Mohammadi-Shemirani, P., Desjardins, E. M., Wang, Z., Tsakiridis, E. E., Lavoie, D. C. T., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.05.004 · Cited by 199 · see citing works
Circadian Rhythms in the Pathogenesis and Treatment of Fatty Liver Disease
Saran, A., Dave, S., & Zarrinpar, A. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.01.050 · Cited by 172 · see citing works
Long noncoding RNA licensing of obesity-linked hepatic lipogenesis and NAFLD pathogenesis
Zhao, X.-Y., Xiong, X., Liu, T., Mi, L., Peng, X., Rui, C., Guo, L., Li, S., Li, X., & Lin, J. D. (2018) · Nature Communications · doi:10.1038/s41467-018-05383-2 · Cited by 159 · see citing works
Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinomaPreprint
Dayton, T. L., Gocheva, V., Miller, K. M., Israelsen, W. J., Bhutkar, A. J., Clish, C. B., Davidson, S. M., Luengo, A., Bronson, R. T., Jacks, T., et al. (2016) · Genes & Development · doi:10.1101/gad.278549.116 · Cited by 158 · see citing works
“For example, up-regulation of Srebf1 has been shown to result in increased hepatic triglyceride levels and is one of the early and primary changes observed in liver-specific Pten knockoutmice, which also develop HCC (Horie et al. 2004; Ueki et al. 2004; Knebel et al. 2012).”
Background
Mechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver
Jelenik, T., Kaul, K., Séquaris, G., Flögel, U., Phielix, E., Kotzka, J., Knebel, B., Fahlbusch, P., Hörbelt, T., Lehr, S., et al. (2017) · Diabetes · doi:10.2337/db16-1147 · Cited by 154 · see citing works
“Animals Female transgenic mice, 18 and 36 weeks of age, with NAFL resulting from PRIM-specific (19) or SEC-specific (20) overexpression of the SREBP-1c, and matched C57Bl6 controls (CON) were maintained under pathogen-free conditions on a 12-h light-dark cycle and received rodent diet (Ssniff M-Z Extrudat, 4.”
MethodSelf-citation
Nonalcoholic fatty liver disease: A main driver of insulin resistance or a dangerous liaison?
Gruben, N., Shiri‐Sverdlov, R., Koonen, D. P. Y., & Hofker, M. H. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.08.004 · Cited by 153 · see citing works
Lipid oxidation products in the pathogenesis of non-alcoholic steatohepatitis
Bellanti, F., Villani, R., Facciorusso, A., Vendemiale, G., & Serviddio, G. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.01.023 · Cited by 132 · see citing works
“expression of transcriptionally active SREBP-1c is associated with hepatic steatosis [191].”
In Vitro and In Vivo Models of Non-Alcoholic Fatty Liver Disease: A Critical Appraisal
Soret, P.-A., Magusto, J., Housset, C., & Gautheron, J. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm10010036 · Cited by 121 · see citing works
Liver Clock Protein BMAL1 Promotes de Novo Lipogenesis through Insulin-mTORC2-AKT Signaling
Zhang, D., Tong, X., Arthurs, B., Guha, A., Rui, L., Kamath, A., Inoki, K., & Yin, L. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.567628 · Cited by 113 · see citing works
Endoplasmic reticulum stress leads to lipid accumulation through upregulation of SREBP-1c in normal hepatic and hepatoma cells
Fang, D., Wan, Y., Shen, W., Cao, J., Sun, Z.-X., Yu, H., Zhang, Q., Cheng, W., Chen, J., & Ning, B. (2013) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-013-1694-7 · Cited by 114 · see citing works
“NAFLD is one of the most frequent causes of abnormal liver function [1].”
BackgroundInfluential
Metabolic-associated fatty liver disease: a selective review of pathogenesis, diagnostic approaches, and therapeutic strategies
Habibullah, M., Jemmieh, K., Ouda, A., Haider, M. Z., Malki, M. I., & Elzouki, A.-N. Y. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1291501 · Cited by 112 · see citing works
Xanthohumol Improves Diet-induced Obesity and Fatty Liver by Suppressing Sterol Regulatory Element-binding Protein (SREBP) Activation
Miyata, S., Inoue, J., Shimizu, M., & Sato, R. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.656975 · Cited by 102 · see citing works
“mice (9, 10), and liver-specific SREBP-1c transgenic mice have displayed hepatic steatosis, hypertriglyceridemia, and insulin resistance (11).”
Background
Can LDL cholesterol be too low? Possible risks of extremely low levels
OLSSON, A. G., Angelin, B., Assmann, G., Binder, C. J., Björkhem, I., Cedazo-Mı́nguez, Á., Cohen, J. C., von Eckardstein, A., Farinaro, E., Müller‐Wieland, D., et al. (2017) · Journal of Internal Medicine · doi:10.1111/joim.12614 · Cited by 99 · see citing works
Preventing High Fat Diet-induced Obesity and Improving Insulin Sensitivity through Neuregulin 4 Gene Transfer
Ma, Y., Gao, M., & Liu, D. (2016) · Scientific Reports · doi:10.1038/srep26242 · Cited by 98 · see citing works
Substrate channeling in the glycerol-3-phosphate pathway regulates the synthesis, storage and secretion of glycerolipids
Lee, J., & Ridgway, N. D. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2019.03.010 · Cited by 93 · see citing works
Melatonin Effects on Non-Alcoholic Fatty Liver Disease Are Related to MicroRNA-34a-5p/Sirt1 Axis and Autophagy
Stacchiotti, A., Grossi, I., García-Gómez, R., Patel, G. A., Salvi, A., Lavazza, A., Petro, G. D., Monsalve, M., & Rezzani, R. (2019) · Cells · doi:10.3390/cells8091053 · Cited by 93 · see citing works
“Mice over-expressing SREBP1c developed a fatty liver even under a normocaloric diet [69].”
Background
Agonist of RORA Attenuates Nonalcoholic Fatty Liver Progression in Mice via Up-regulation of MicroRNA 122
Chai, C., Cox, B. D., Yaish, D., Gross, D., Rosenberg, N., Amblard, F., Shemuelian, Z., Gefen, M., Korach, A., Tirosh, O., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.05.056 · Cited by 83 · see citing works
“On the other hand, the expression levels of genes that are involved in FFA biosynthesis pathways and are associated with fatty liver (Fasn and Srebf1) 12,13 and are negatively correlated with RORA (Figure 2D).”
Background
Hepatic growth hormone - JAK2 - STAT5 signalling: Metabolic function, non-alcoholic fatty liver disease and hepatocellular carcinoma progression
Kaltenecker, D., Themanns, M., Mueller, K. M., Spirk, K., Suske, T., Merkel, O., Kenner, L., Luís, A., Kozlov, A. V., Haybaeck, J., et al. (2018) · Cytokine · doi:10.1016/j.cyto.2018.10.010 · Cited by 80 · see citing works
De Novo Lipogenesis Products and Endogenous Lipokines
Yilmaz, M., Claiborn, K. C., & Hotamışlıgil, G. S. (2016) · Diabetes · doi:10.2337/db16-0251 · Cited by 70 · see citing works
“In fact, loss- and gain-offunction studies indicate that SREBP1 functions as an important regulator of DNL in the liver (4,5).”
Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2
Bathish, B., Robertson, H., Dillon, J. F., Dinkova‐Kostova, A. T., & Hayes, J. D. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.06.226 · Cited by 68 · see citing works
Pathophysiology of NAFLD and NASH in Experimental Models: The Role of Food Intake Regulating Peptides
Kořínková, L., Pražienková, V., Černá, L., Karnošová, A., Železná, B., Kuneš, J., & Maletı́nská, L. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.597583 · Cited by 68 · see citing works
“↑ TG ↑ FFA, ↑ insulin (serum), steatosis (48, 49)”
Background
Brg1 regulates pro-lipogenic transcription by modulating SREBP activity in hepatocytes
Li, N., Li, M., Hong, W., Shao, J., Xu, H., Shimano, H., Lu, J. L., & Xu, Y. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.05.022 · Cited by 65 · see citing works
Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction
Fujii, N., Narita, T., Okita, N., Kobayashi, M., Furuta, Y., Chujo, Y., Sakai, M., Yamada, A., Takeda, K., Konishi, T., et al. (2017) · Aging Cell · doi:10.1111/acel.12576 · Cited by 64 · see citing works
“In contrast to that, however, certain reports suggested that CR did not induce mitochondrial biogenesis or increase mitochondrial content (Hempenstall et al., 2012; Lanza et al., 2012).”
Estrogen Signalling and the Metabolic Syndrome: Targeting the Hepatic Estrogen Receptor Alpha Action
Matic, M., Bryzgalova, G., Gao, H., Antonson, P., Humire, P., Omoto, Y., Portwood, N., Pramfalk, C., Efendić, S., Berggren, P., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057458 · Cited by 62 · see citing works
“We also examined hepatic transcript levels of SREBP-1c, a classic indicator of hepatic steatosis [33,34,35].”
Background
Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions
Leslie, J., Geh, D., Elsharkawy, A. M., Mann, D. A., & Vacca, M. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.01.029 · Cited by 61 · see citing works
Time-dependent Changes and Association Between Liver Free Fatty Acids, Serum Lipid Profile and Histological Features in Mice Model of Nonalcoholic Fatty Liver Disease
Stanković, M. N., Mladenović, D. R., Djuricic, I. D., Sobajic, S. S., Timić, J., Jorgačević, B. Z., Aleksić, V., Vučević, D. B., Ješić-Vukićević, R., & Radosavljević, T. S. (2014) · Archives of Medical Research · doi:10.1016/j.arcmed.2013.12.010 · Cited by 58 · see citing works
Developmental and extrahepatic physiological functions of SREBP pathway genes in mice
Engelking, L. J., Cantoria, M. J., Xu, Y., & Liang, G. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.07.011 · Cited by 56 · see citing works
Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis
Hu, Y., Liu, X., & Zhan, W. (2018) · Drug Design Development and Therapy · doi:10.2147/dddt.s170518 · Cited by 60 · see citing works
“One key transcription factor in DNL is sterol regulatory element-binding protein-1c (SREBP-1c).(19) The result of RTqPCR showed that SREBP-1c mRNA was induced in the vehicle group compared to the NC group, and downregulated by INT-767 treatment (Figure 4G).”
Background
Insulin Resistance, Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Clinical and Experimental Perspective
Jung, I., Koo, D.-J., & Lee, W. (2024) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2023.0350 · Cited by 56 · see citing works
Ghrelin function in human obesity and type 2 diabetes: a concise review
Churm, R., Davies, J. S., Stephens, J. W., & Prior, S. L. (2017) · Obesity Reviews · doi:10.1111/obr.12474 · Cited by 58 · see citing works
“SREBP1 is encoded by the SREBF1 gene, which is transcribed into two splice variants, SREBP1-a and SREBP1-c (48).”
Background
Disrupted Blood-Retina Lysophosphatidylcholine Transport Impairs Photoreceptor Health But Not Visual Signal Transduction
Lobanova, E. S., Schuhmann, K., Finkelstein, S., Lewis, T. R., Cady, M. A., Hao, Y., Keuthan, C. J., Ash, J. D., Burns, M. E., Shevchenko, A., et al. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.1142-19.2019 · Cited by 56 · see citing works
“…Stearoyl-CoA desaturases 1 and 2 (Scd1 and Scd2), fatty acid desaturases 1 and 2 (Fads1 and Fads2), as well as sterol regulatory element-binding factor Srebf1, which reported to control their expression in other experimental systems (Seo et al., 2009; Knebel et al., 2012; Angela et al., 2016; Fig.”
Background
Ellagic acid protects against non-alcoholic fatty liver disease in streptozotocin-diabetic rats by activating AMPK
ALTAMIMI, J. Z., Alshammari, G. M., AlFaris, N. A., Alagal, R. I., ALJABRYN, D. H., Albekairi, N. A., Alkhateeb, M. A., & Yahya, M. A. (2021) · Pharmaceutical Biology · doi:10.1080/13880209.2021.1990969 · Cited by 54 · see citing works
“SREBP1 and SREBP2 transcription factors, respectively (Tomita et al. 2005; Yang et al. 2009; Knebel et al. 2012; Quan et al. 2013; Tang et al. 2016; de Souza et al. 2017; Ren et al. 2019).”
Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis
Bai, X., Hong, W., Cai, P., Chen, Y., Xu, C., Cao, D., Yu, W., Zhao, Z., Huang, M., & Jin, J. (2017) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2017.03.022 · Cited by 53 · see citing works
Phosphorylation of sterol regulatory element-binding protein (SREBP)-1c by p38 kinases, ERK and JNK influences lipid metabolism and the secretome of human liver cell line HepG2
Knebel, B., Lehr, S., Hartwig, S., Haas, J., Kaber, G., Dicken, H.-D., Susanto, F., Bohne, L., Jacob, S., Nitzgen, U., et al. (2014) · Archives of Physiology and Biochemistry · doi:10.3109/13813455.2014.973418 · Cited by 53 · see citing works
“…in a mouse model that liverspecific over-expression of the N-terminal domain of SREBP1c (alb-SREBP-1c) results in mild fatty liver, obesity, altered body composition, altered lipid profile in the liver and reduced insulin sensitivity without additional physiological stress (Knebel et al., 2012).”
BackgroundMethodResultInfluentialSelf-citation
Impact of sterol regulatory element-binding factor-1c polymorphism on incidence of nonalcoholic fatty liver disease and on the severity of liver disease and of glucose and lipid dysmetabolism
Musso, G., Bo, S., Cassader, M., Michieli, F. D., & Gambino, R. (2013) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.063792 · Cited by 51 · see citing works
The molecular pathogenic role of inflammatory stress in dysregulation of lipid homeostasis and hepatic steatosis
Chen, Y., Varghese, Z., & Ruan, X. Z. (2014) · Genes & Diseases · doi:10.1016/j.gendis.2014.07.007 · Cited by 54 · see citing works
“Sterol regulatory element-binding protein-1,2 (SREBP-1,2) are nuclear transcription factors that transcriptionally activate genes involved in de novo lipogenesis.(38,39) The acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) are important downstream target genes of SREBP-1, which are the rate-limiting enzymes…”
Background
Urolithins Attenuate Multiple Symptoms of Obesity in Rats Fed on a High-Fat Diet
Abdulrahman, A. O., Kuerban, A., Alshehri, Z. A., Abdulaal, W. H., Khan, J. A., & Khan, M. I. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s268146 · Cited by 50 · see citing works
β2-spectrin (SPTBN1) as a therapeutic target for diet-induced liver disease and preventing cancer development
Rao, S., Yang, X., Ohshiro, K., Zaidi, S., Wang, Z., Shetty, K., Xiang, X., Hassan, M. I., Mohammad, T., Latham, P. S., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abk2267 · Cited by 47 · see citing works
The Endoplasmic Reticulum Coat Protein II Transport Machinery Coordinates Cellular Lipid Secretion and Cholesterol Biosynthesis
Fryer, L. G. D., Jones, B., Duncan, E. J., Hutchison, C. E., Ozkan, T., Williams, P. A., Alder, O., Nieuwdorp, M., Townley, A. K., Mensenkamp, A. R., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.479980 · Cited by 46 · see citing works
Glutathione disulfide sensitizes hepatocytes to TNFα-mediated cytotoxicity via IKK-β S-glutathionylation: a potential mechanism underlying non-alcoholic fatty liver disease
Dou, X., Li, S., Hu, L., Ding, L., Ma, Y., Ma, W., Chai, H., & Song, Z. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-017-0013-x · Cited by 46 · see citing works
Lyophilized Maqui (Aristotelia chilensis) Berry Induces Browning in the Subcutaneous White Adipose Tissue and Ameliorates the Insulin Resistance in High Fat Diet-Induced Obese Mice
Sandoval, V., Femenias, A., Martínez‐Garza, Ú., Sanz‐Lamora, H., Castagnini, J. M., Quifer‐Rada, P., Lamuela-Raventós, R. M., Marrero, P. F., Haro, D., & Relat, J. (2019) · Antioxidants · doi:10.3390/antiox8090360 · Cited by 46 · see citing works
Fatty Liver Due to Increased de novo Lipogenesis: Alterations in the Hepatic Peroxisomal Proteome
Knebel, B., Fahlbusch, P., Dille, M. A., Wahlers, N., Hartwig, S., Jacob, S., Kettel, U., Schiller, M., Herebian, D. A., Koellmer, C., et al. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00248 · Cited by 44 · see citing works
“Since the expression of the intrinsic SREBP-1c molecule is not increased (Knebel et al., 2012), a feedback loop might be active to compensate for the overrepresentation of the human SREBP molecule.”
BackgroundMethodResultInfluentialSelf-citation
The protective mechanisms of macroalgae <i>Laminaria japonica</i> consumption against lipid metabolism disorders in high-fat diet-induced hyperlipidemic rats
Zhang, Q., Fan, X.-Y., Guo, W.-L., Cao, Y.-J., Lin, Y.-C., Cheng, W.-J., Chen, L.-J., Rao, P.-F., Ni, L., & Lv, X.-C. (2020) · Food & Function · doi:10.1039/d0fo00065e · Cited by 42 · see citing works
Hsp90 modulates PPARγ activity in a mouse model of nonalcoholic fatty liver disease
Wheeler, M. C., & Gekakis, N. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m048918 · Cited by 42 · see citing works
Protectin DX Ameliorates Hepatic Steatosis by Suppression of Endoplasmic Reticulum Stress via AMPK-Induced ORP150 Expression
Jung, T. W., Kyung, E. J., Kim, H., Shin, Y. K., Lee, S. H., Park, E. S., Hacımüftüoğlu, A., El‐Aty, A. M. A., & Jeong, J. H. (2018) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.117.246686 · Cited by 42 · see citing works
Epigenetic regulation of the ELOVL6 gene is associated with a major QTL effect on fatty acid composition in pigs
Corominas, J., Marchesi, J. A. P., Puig-Oliveras, A., Revilla, M., Estellé, J., Alves, E., Folch, J. M., & Ballester, M. (2015) · Genetics Selection Evolution · doi:10.1186/s12711-015-0111-y · Cited by 40 · see citing works
“genes involved in de novo lipogenesis [11].”
Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men
Fahlbusch, P., Knebel, B., Hörbelt, T., Barbosa, D. M., Nikolic, A., Jacob, S., Al‐Hasani, H., de Velde, F. V., Nieuwenhove, Y. V., Müller‐Wieland, D., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21114144 · Cited by 40 · see citing works
“IGF1 incubation enhanced DNL in aP2-SREBP-1c phenotypes, yet this stimulatory effect was not observed when IGF1 was pre-incubated with IGFBP2 (Figure 5D).”
BackgroundMethodInfluentialSelf-citation
Lipodystrophies—Disorders of the Fatty Tissue
Knebel, B., Müller-Wieland, D., & Kotzka, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228778 · Cited by 39 · see citing works
Self-citation
Zinc mediates the SREBP-SCD axis to regulate lipid metabolism in Caenorhabditis elegans
Zhang, J., Hao, J., Zhang, Y., Wang, Y., Li, M., Miao, H., Zou, X.-J., & Liang, B. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m077198 · Cited by 37 · see citing works
Saponin from sea cucumber exhibited more significant effects than ginsenoside on ameliorating high fat diet-induced obesity in C57BL/6 mice
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BackgroundInfluential
SRY-Box Containing Gene 4 Promotes Liver Steatosis by Upregulation of SREBP-1c
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Investigating fatty liver disease-associated adverse outcome pathways of perfluorooctane sulfonate using a systems toxicology approach
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Maternal diet amplifies the hepatic aging trajectory of Cidea in male mice and leads to the development of fatty liver
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Pinolenic Acid Downregulates Lipid Anabolic Pathway in HepG2 Cells
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Authors: Knebel, B., Haas, J., Hartwig, S., Jacob, S., Köllmer, C., Nitzgen, U., Muller–Wieland, D., & Kotzka, J.
Affiliations: Deutsches Diabetes-Zentrum e.V. (DE)
Asklepios Klinik St. Georg (DE)
ORCID: Knebel, Birgit
Hartwig, Sonja
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2012-02-21
Volume: 7
Issue: 2
Pages: e31812
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0031812
PMC: PMC3283692
OpenAlex: W2015190417
Cited by: 162
References: 68
Citations by year: 2026: 7 · 2025: 8 · 2024: 12 · 2023: 12 · 2022: 12 · 2021: 11 · 2020: 14 · 2019: 11 · 2018: 17 · 2017: 12 · 2016: 11 · 2015: 9 · 2014: 13 · 2013: 9 · 2012: 4
FWCI: 8.35
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords: SREBP-1c, hepatic steatosis, visceral fat, de novo lipogenesis, hepatic lipid accumulation, insulin resistance, transgenic mouse model, fatty acid composition, triglycerides, free fatty acids, lipid metabolism, metabolic disorders
MeSH terms: Fatty Acid Elongases, Acetyltransferases, Animals, Body Composition, Fatty Acids, Fatty Liver, Gene Expression Regulation, Humans, Insulin, Insulin Resistance, Liver, Male, Mice, Transgenic, Organ Specificity, Organ Size, Phenotype, Stearoyl-CoA Desaturase, Transcription, Genetic, Cytokines, Protein Structure, Tertiary, Adipocytes, Intra-Abdominal Fat, Adiposity, Lipogenesis, Mice, Sterol Regulatory Element Binding Protein 1

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Liver-specific expression of transcriptionally active SREBP-1c is associated with fatty liver and increased visceral fat mass

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