Therapeutic strategies targeting SREBP transcription factors: an update to 2024

Abstract

In addition to regulating lipid biosynthesis and uptake, sterol regulatory element binding protein (SREBP) is involved in mediating biological signaling networks. SREBP is a key transcription factor in the regulation of physiologic and pathologic lipid metabolism processes. “SREBP” was used as a keyword in searches on the Web of Science, Elsevier, Science Direct, and CNKI databases for relevant literature from 2021 to October 2024; the search results were analyzed. SREBP is first synthesized as an inactive precursor, then cleaved to release active NH₂-terminal domains. Mature SREBP enters the nucleus and promotes transcription of downstream genes by binding to the promoter elements of target genes. The classical pathway of SREBP precursor activation refers to transporter cleavage that is dependent on SCAP in response to signals from intracellular sterol depletion. However, in the case of endoplasmic reticulum stress, SREBP is activated via caspase-2 and independent of feedback inhibition by steroids or excess lipid uptake. Furthermore, the mechanism of action underlying SREBP in different diseases, as well as synthetic and natural compounds that inhibit SREBP activity, are summarized to provide new insights into SREBP as a therapeutic target for diseases.

Keywords

SREBPs / metabolism regulation / related diseases / therapeutic strategies

References

[1] Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, et al.: SREBP-1, a Basic-Helix-loop-helix-leucine Zipper Protein that Controls Transcription of the Low Density Lipoprotein Receptor Gene. Cell 1993, 75: 187-197.

[2] Brown MS, Goldstein JL: The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-bound Transcription Factor. Cell 1997, 89: 331-340.

[3] Hua X, Sakai J, Ho YK, Goldstein JL, Brown MS: Hairpin Orientation of Sterol Regulatory Element-binding Protein-2 in Cell Membranes as Determined by Protease Protection. The Journal of Biological Chemistry 1995, 270: 29422-29427.

[4] Kober DL, Radhakrishnan A, Goldstein JL, Brown MS, Clark LD, Bai XC, et al.: Scap Structures Highlight Key Role for Rotation of Intertwined Luminal Loops in Cholesterol Sensing. Cell 2021, 184: 3689-3701.e3622.

[5] Yan R, Cao P, Song W, Li Y, Wang T, Qian H, et al.: Structural Basis for Sterol Sensing by Scap and Insig. Cell Reports 2021, 35: 109299.

[6] Yan R, Cao P, Song W, Qian H, Du X, Coates HW, et al.: A Structure of Human Scap Bound to Insig-2 Suggests How Their Interaction is Regulated by Sterols. Science 2021, 371: eabb2224.

[7] Ren R, Zhou X, He Y, Ke M, Wu J, Liu X, et al.: PROTEIN STRUCTURE. Crystal Structure of a Mycobacterial Insig Homolog Provides Insight into How These Sensors Monitor Sterol Levels. Science 2015, 349: 187-191.

[8] Cheng C, Ru P, Geng F, Liu J, Yoo JY, Wu X, et al.: Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth. Cancer Cell 2015, 28: 569-581.

[9] Cheng C, Geng F, Li Z, Zhong Y, Wang H, Cheng X, et al.: Ammonia Stimulates SCAP/Insig Dissociation and SREBP-1 Activation to Promote Lipogenesis and Tumour Growth. Nature Metabolism 2022, 4: 575-588.

[10] Su L, Zhou L, Chen FJ, Wang H, Qian H, Sheng Y, et al.: Cideb Controls Sterol-regulated ER Export of SREBP/SCAP by Promoting Cargo Loading at ER Exit Sites. EMBO J 2019, 38: e100156.

[11] Huang Y, Wang YF, Ruan XZ, Lau CW, Wang L, Huang Y: The Role of KLF2 in Regulating Hepatic Lipogenesis and Blood Cholesterol Homeostasis via the SCAP/SREBP Pathway. Journal of Lipid Research 2024, 65: 100472.

[12] Kong M, Zhu Y, Shao J, Fan Z, Xu Y: The Chromatin Remodeling Protein BRG1 Regulates SREBP Maturation by Activating SCAP Transcription in Hepatocytes. Frontiers in Cell and Developmental Bology 2021, 9: 622866.

[13] Brown MS, Radhakrishnan A, Goldstein JL: Retrospective on Cholesterol Homeostasis: The Central Role of Scap. Annual Review of Biochemistry 2018, 87: 783-807.

[14] Yabe D, Komuro R, Liang G, Goldstein JL, Brown MS: Liver-specific mRNA for Insig-2 Down-regulated by Insulin: Implications for Fatty Acid Synthesis. Proceedings of the National Academy of Sciences of the United States of America 2003, 100: 3155-3160.

[15] Zhang F, Hu Z, Li G, Huo S, Ma F, Cui A, et al.: Hepatic CREBZF Couples Insulin to Lipogenesis by Inhibiting Insig Activity and Contributes to Hepatic Steatosis in Diet-Induced Insulin-Resistant Mice. Hepatology 2018, 68: 1361-1375.

[16] Zeng H, Qin H, Liao M, Zheng E, Luo X, Xiao A, et al.: CD36 Promotes De Novo Lipogenesis in Hepatocytes Through INSIG2-dependent SREBP1 Processing. Molecular Metabolism 2022, 57: 101428.

[17] Xu D, Wang Z, Zhang Y, Jiang W, Pan Y, Song BL, et al.: PAQR3 Modulates Cholesterol Homeostasis by Anchoring Scap/SREBP Complex to the Golgi Apparatus. Nature Communications 2015, 6: 8100.

[18] Loregger A, Raaben M, Nieuwenhuis J, Tan JME, Jae LT, van den Hengel LG, et al.: Haploid Genetic Screens Identify SPRING/C12ORF49 as a Determinant of SREBP Signaling and Cholesterol Metabolism. Nature Communications 2020, 11: 1128.

[19] Hendrix S, Kingma J, Ottenhoff R, Valiloo M, Svecla M, Zijlstra LF, et al.: Hepatic SREBP Signaling Requires SPRING to Govern Systemic Lipid Metabolism in Mice and Humans. Nature Communications 2023, 14: 5181.

[20] Amemiya-Kudo M, Shimano H, Yoshikawa T, Yahagi N, Hasty AH, Okazaki H, et al.: Promoter Analysis of the Mouse Sterol Regulatory Element-binding Protein-1c Gene. The Journal of Biological Chemistry 2000, 275: 31078-31085.

[21] Xiong S, Chirala SS, Wakil SJ: Sterol Regulation of Human Fatty Acid Synthase Promoter I Requires Nuclear Factor-Y-and Sp-1-Binding Sites. Proceedings of the National Academy of Sciences of the United States of America 2000, 97: 3948-3953.

[22] Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, et al.: Regulation of Mouse Sterol Regulatory Element-binding Protein-1c Gene (SREBP-1c) by Oxysterol Receptors, LXRalpha and LXRbeta. Genes and Development 2000, 14: 2819-2830.

[23] Ferré P, Phan F, Foufelle F: SREBP-1c and Lipogenesis in the Liver: An Update1. The Biochemical Journal 2021, 478: 3723-3739.

[24] Tian J, Goldstein JL, Brown MS: Insulin Induction of SREBP-1c in Rodent Liver Requires LXRα-C/EBPβ Complex. Proceedings of the National Academy of Sciences of the United States of America 2016, 113: 8182-8187.

[25] Tian J, Wu J, Chen X, Guo T, Chen ZJ, Goldstein JL, et al.: BHLHE40, a Third Transcription Factor Required for Insulin Induction of SREBP-1c mRNA in Rodent Liver. Elife 2018, 7: e36826.

[26] Seo HY, Kim MK, Jung YA, Jang BK, Yoo EK, Park KG, et al.: Clusterin Decreases Hepatic SREBP-1c Expression and Lipid Accumulation. Endocrinology 2013, 154: 1722-1730.

[27] Kim JY, Wang LQ, Sladky VC, Oh TG, Liu J, Trinh K, et al.: PIDDosome-SCAP Crosstalk Controls High-fructose-diet-dependent Transition from Simple Steatosis to Steatohepatitis. Cell Metabolism 2022, 34: 1548-1560.e1546.

[28] Kim JY, Garcia-Carbonell R, Yamachika S, Zhao P, Dhar D, Loomba R, et al.: ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P. Cell 2018, 175: 133-145.e115.

[29] Jiang T, Zhang G, Lou Z: Role of the Sterol Regulatory Element Binding Protein Pathway in Tumorigenesis. Frontiers in Oncology 2020, 10: 1788.

[30] Metón I, Egea M, Anemaet IG, Fernández F, Baanante IV: Sterol Regulatory Element Binding Protein-1a Transactivates 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase Gene Promoter. Endocrinology 2006, 147: 3446-3456.

[31] Nguyen TTP, Kim DY, Lee YG, Lee YS, Truong XT, Lee JH, et al.: SREBP-1c Impairs ULK1 Sulfhydration-mediated Autophagic Flux to Promote Hepatic Steatosis in High-fat-diet-fed Mice. Molecular Cell 2021, 81: 3820-3832.e3827.

[32] Lee G, Kim YY, Jang H, Han JS, Nahmgoong H, Park YJ et al.: SREBP1c-PARP1 Axis Tunes Anti-senescence Activity of Adipocytes and Ameliorates Metabolic Imbalance in Obesity. Cell Metabolism 2022, 34: 702-718.e705.

[33] Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al.: Cellular Senescence: Defining a Path Forward. Cell 2019, 179: 813-827.

[34] Field FJ, Born E, Murthy S, Mathur SN: Regulation of Sterol Regulatory Element-binding Proteins in Hamster Intestine by Changes in Cholesterol Flux. The Journal of Biological Chemistry 2001, 276: 17576-17583.

[35] Horton JD, Shimomura I, Ikemoto S, Bashmakov Y, Hammer RE: Overexpression of Sterol Regulatory Element-binding Protein-1a in Mouse Adipose Tissue Produces Adipocyte Hypertrophy, Increased Fatty Acid Secretion, and Fatty Liver. The Journal of Biological Chemistry 2003, 278: 36652-36660.

[36] Iwasaki Y, Iwasaki H, Yatoh S, Ishikawa M, Kato T, Matsuzaka T, et al.: Nuclear SREBP-1a Causes Loss of Pancreatic Beta-cells and Impaired Insulin Secretion. Biochemical and Biophysical Research Communications 2009, 378: 545-550.

[37] Geng F, Zhong Y, Su H, Lefai E, Magaki S, Cloughesy TF, et al.: SREBP-1 Upregulates Lipophagy to Maintain Cholesterol Homeostasis in Brain Tumor Cells. Cell Reports 2023, 42: 112790.

[38] Shimomura I, Bashmakov Y, Horton JD: Increased Levels of Nuclear SREBP-1c Associated with Fatty Livers in Two Mouse Models of Diabetes Mellitus. The Journal of Biological Chemistry 1999, 274: 30028-30032.

[39] Yahagi N, Shimano H, Hasty AH, Matsuzaka T, Ide T, Yoshikawa T, et al.: Absence of Sterol Regulatory Element-binding Protein-1 (SREBP-1) Ameliorates Fatty Livers but not Obesity or Insulin Resistance in Lep(ob)/Lep(ob) Mice. The Journal of Biological Chemistry 2002, 277: 19353-19357.

[40] Shimano H, Shimomura I, Hammer RE, Herz J, Goldstein JL, Brown MS, et al.: Elevated Levels of SREBP-2 and Cholesterol Synthesis in Livers of Mice Homozygous for a Targeted Disruption of the SREBP-1 Gene. The Journal of Clinical Investigation 1997, 100: 2115-2124.

[41] Oishi Y, Spann NJ, Link VM, Muse ED, Strid T, Edillor C, et al.: SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism. Cell Metabolism 2017, 25: 412-427.

[42] Li X, Huang W, Gu J, Du X, Lei L, Yuan X, et al.: SREBP-1c Overactivates ROS-mediated Hepatic NF-κB Inflammatory Pathway in Dairy Cows with Fatty Liver. Cell Signal 2015, 27: 2099-2109.

[43] Amemiya-Kudo M, Shimano H, Hasty AH, Yahagi N, Yoshikawa T, Matsuzaka T, et al.: Transcriptional Activities of Nuclear SREBP-1a, -1c, and -2 to Different Target Promoters of Lipogenic and Cholesterogenic Genes. Journal of Lipid Research 2002, 43: 1220-1235.

[44] Wolfrum C, Stoffel M: Coactivation of Foxa2 through Pgc-1beta Promotes Liver Fatty Acid Oxidation and Triglyceride/VLDL Secretion. Journal of Lipid Research 2006, 3: 99-110.

[45] Han J, Li E, Chen L, Zhang Y, Wei F, Liu J, et al.: The CREB Coactivator CRTC2 Controls Hepatic Lipid Metabolism by Regulating SREBP1. Nature 2015, 524: 243-246.

[46] Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun ZY, Watts JL, et al.: An ARC/Mediator Subunit Required for SREBP Control of Cholesterol and Lipid Homeostasis. Nature 2006, 442: 700-704.

[47] Archer A, Venteclef N, Mode A, Pedrelli M, Gabbi C, Clément K, et al.: Fasting-induced FGF21 is Repressed by LXR Activation via Recruitment of an HDAC3 Corepressor Complex in Mice. Molecular Endocrinology 2012, 26: 1980-1990.

[48] Giandomenico V, Simonsson M, Grönroos E, Ericsson J: Coactivator-dependent Acetylation Stabilizes Members of the SREBP Family of Transcription Factors. Molecular and Cellular Biology 2003, 23: 2587-2599.

[49] Paluvai H, Shanmukha KD, Tyedmers J, Backs J: Insights into the Function of HDAC3 and NCoR1/NCoR2 Co-repressor Complex in Metabolic Diseases. Frontiers in Molecular Biosciences 2023, 10: 1190094.

[50] Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, et al.: SIRT1 Deacetylates and Inhibits SREBP-1C Activity in Regulation of Hepatic Lipid Metabolism. The Journal of Biological Chemistry 2010, 285: 33959-33970.

[51] Chen J, Zhou Y, Liu Z, Lu Y, Jiang Y, Cao K, et al.: Hepatic Glycogenesis Antagonizes Lipogenesis by Blocking S1P via UDPG. Science 2024, 383: eadi3332.

[52] Krycer JR, Sharpe LJ, Luu W, Brown AJ: The Akt-SREBP Nexus: Cell Signaling Meets Lipid Metabolism. Trends in Endocrinology and Metabolism 2010, 21: 268-276.

[53] Yamauchi Y, Furukawa K, Hamamura K, Furukawa K: Positive Feedback Loop Between PI3K-Akt-mTORC1 Signaling and the Lipogenic Pathway Boosts Akt Signaling: Induction of the Lipogenic Pathway by a Melanoma Antigen. Cancer Research 2011, 71: 4989-4997.

[54] Owen JL, Zhang Y, Bae SH, Farooqi MS, Liang G, Hammer RE, et al.: Insulin Stimulation of SREBP-1c Processing in Transgenic Rat Hepatocytes Requires p70 S6-kinase. Proceedings of the National Academy of Sciences of the United States of America 2012, 109: 16184-16189.

[55] Hwahng SH, Ki SH, Bae EJ, Kim HE, Kim SG: Role of Adenosine Monophosphate-activated Protein Kinase-p70 Ribosomal S6 Kinase-1 Pathway in Repression of Liver X Receptor-alpha-dependent Lipogenic Gene Induction and Hepatic Steatosis by a Novel Class of Dithiolethiones. Hepatology 2009, 49: 1913-1925.

[56] Male V, Nisoli I, Gascoyne DM, Brady HJ: E4BP4: An Unexpected Player in the Immune Response. Trends in Immunology 2012, 33: 98-102.

[57] Hatori M, Hirota T, Iitsuka M, Kurabayashi N, Haraguchi S, Kokame K, et al.: Light-dependent and Circadian Clock-regulated Activation of Sterol Regulatory Element-binding Protein, X-box-binding Protein 1, and Heat Shock Factor Pathways. Proceedings of the National Academy of Sciences of the United States of America 2011, 108: 4864-4869.

[58] Tong X, Li P, Zhang D, VanDommelen K, Gupta N, Rui L, et al.: E4BP4 is an Insulin-induced Stabilizer of Nuclear SREBP-1c and Promotes SREBP-1c-mediated Lipogenesis. Journal of Lipid Research 2016, 57: 1219-1230.

[59] Gilardi F, Migliavacca E, Naldi A, Baruchet M, Canella D, Le Martelot G, et al.: Genome-wide Analysis of SREBP1 Activity Around the Clock Reveals its Combined Dependency on Nutrient and Circadian Signals. PLoS Genetics 2014, 10: e1004155.

[60] Cho S, Chun Y, He L, Ramirez CB, Ganesh KS, Jeong K, et al.: FAM120A Couples SREBP-dependent Transcription and Splicing of Lipogenesis Enzymes Downstream of mTORC1. Molecular Cell 2023, 83: 3010-3026.e3018.

[61] Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, et al.: mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway. Cell 2011, 146: 408-420.

[62] Sundqvist A, Bengoechea-Alonso MT, Ye X, Lukiyanchuk V, Jin J, Harper JW, et al.: Control of Lipid Metabolism by Phosphorylation-Dependent Degradation of the Srebp Family Of Transcription Factors by SCF(Fbw7). Cell Metabolism 2005, 1: 379-391.

[63] Yecies JL, Zhang HH, Menon S, Liu S, Yecies D, Lipovsky AI, et al.: Akt Stimulates Hepatic SREBP1c and Lipogenesis through Parallel mTORC1-dependent and Independent Pathways. Cell Metabolism 2011, 14: 21-32.

[64] Gosis BS, Wada S, Thorsheim C, Li K, Jung S, Rhoades JH, et al.: Inhibition of Nonalcoholic Fatty Liver Disease in Mice by Selective Inhibition of mTORC1. Science 2022, 376: eabf8271.

[65] Baiceanu A, Mesdom P, Lagouge M, Foufelle F: Endoplasmic Reticulum Proteostasis in Hepatic Steatosis. Nature Reviews. Endocrinology 2016, 12: 710-722.

[66] Lee JN, Ye J: Proteolytic Activation of Sterol Regulatory Element-binding Protein Induced by Cellular Stress through Depletion of Insig-1. The Journal of Biological Chemistry 2004, 279: 45257-45265.

[67] Bobrovnikova-Marjon E, Hatzivassiliou G, Grigoriadou C, Romero M, Cavener DR, Thompson CB, et al.: PERK-dependent Regulation of Lipogenesis During Mouse Mammary Gland Development and Adipocyte Differentiation. Proceedings of the National Academy of Sciences of the United States of America 2008, 105: 16314-16319.

[68] Gurcel L, Abrami L, Girardin S, Tschopp J, van der Goot FG: Caspase-1 Activation of Lipid Metabolic Pathways In Response to Bacterial Pore-Forming Toxins Promotes Cell Survival. Cell 2006, 126: 1135-1145.

[69] Cheng Y, Manabe I, Hayakawa S, Endo Y, Oishi Y: Caspase-11 Contributes to Site-1 Protease Cleavage and SREBP1 Activation in the Inflammatory Response of Macrophages. Frontiers in Immunology 2023, 14: 1009973.

[70] Mohammadpour-Asl S, Roshan-Milani B, Roshan-Milani S, Roshan-Milani S, Saboory E, Ghobadian B, et al.: Endoplasmic Reticulum Stress PERK-ATF4-CHOP Pathway is Involved in Non-alcoholic Fatty Liver Disease in Type 1 Diabetic Rats: The Rescue Effect Of Treatment Exercise and Insulin-Like Growth Factor I. Heliyon 2024, 10: e27225.

[71] Walker AK, Jacobs RL, Watts JL, Rottiers V, Jiang K, Finnegan DM, et al.: A Conserved SREBP-1/phosphatidylcholine Feedback Circuit Regulates Lipogenesis in Metazoans. Cell 2011, 147: 840-852.

[72] Dibble CC, Manning BD: Signal Integration by mTORC1 Coordinates Nutrient Input with Biosynthetic Output. Nature Cell Biology 2013, 15: 555-564.

[73] Hu X, Guo F: Amino Acid Sensing in Metabolic Homeostasis and Health. Endocrine Reviews 2021, 42: 56-76.

[74] Lin J, Yang R, Tarr PT, Wu PH, Handschin C, Li S, et al.: Hyperlipidemic Effects of Dietary Saturated Fats Mediated through PGC-1beta Coactivation of SREBP. Cell 2005, 120: 261-273.

[75] Kim YR, Lee EJ, Shin KO: Hepatic Triglyceride Accumulation via Endoplasmic Reticulum Stress-induced SREBP-1 Activation is Regulated by Ceramide Synthases. Experimental & Molecular Medicine 2019, 51: 1-16.

[76] Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O: Fatty Acid Regulation of Hepatic Gene Transcription. The Journal of Nutrition 2005, 135: 2503-2506.

[77] Liu X, Xue Y, Liu C, Lou Q, Wang J, Yanagita T, et al.: Eicosapentaenoic Acid-enriched Phospholipid Ameliorates Insulin Resistance and Lipid Metabolism in Diet-induced-obese Mice. Lipids in Health and Disease 2013, 12: 109.

[78] Tian J, Goldstein JL, Li S, Schumacher MM, Brown MS: Phosphorylation of Insig-2 Mediates Inhibition of Fatty Acid Synthesis by Polyunsaturated Fatty Acids. Proceedings of the National Academy of Sciences of the United States of America 2024, 121: e2409262121.

[79] Huang LH, Chung HY, Su HM: Docosahexaenoic Acid Reduces Sterol Regulatory Element Binding Protein-1 and Fatty Acid Synthase Expression and Inhibits Cell Proliferation by Inhibiting pAkt Signaling in a Human Breast Cancer MCF-7 Cell Line. BMC Cancer 2017, 17: 890.

[80] Lee JN, Kim H, Yao H, Chen Y, Weng K, Ye J: Identification of Ubxd8 Protein as a Sensor for Unsaturated Fatty Acids and Regulator of Triglyceride Synthesis. Proceedings of the National Academy of Sciences of the United States of America 2010, 107: 21424-21429.

[81] Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, et al.: AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-induced Insulin-Resistant Mice. Cell Metabolism 2011, 13: 376-388.

[82] Wang H, Zhao M, Sud N, Christian P, Shen J, Song Y, et al.: Glucagon Regulates Hepatic Lipid Metabolism via cAMP and Insig-2 Signaling: Implication for the Pathogenesis of Hypertriglyceridemia and Hepatic Steatosis. Science Reports 2016, 6: 32246.

[83] Zhang Y, Liu Y, Chen L, Wang Y, Han J: CRTC2 Modulates Hepatic SREBP1c Cleavage by Controlling Insig2a Expression During Fasting. Protein Cell 2018, 9: 729-732.

[84] Lee JH, Kang HS, Park HY, Moon YA, Kang YN, Oh BC, et al.: PPARα-dependent Insig2a Overexpression Inhibits SREBP-1c Processing During Fasting. Science Reports 2017, 7: 9958.

[85] Lu M, Shyy JY: Sterol Regulatory Element-binding Protein 1 is Negatively Modulated by PKA Phosphorylation. American Journal of Physiology. Cell Physiology 2006, 290: C1477-C1486.

[86] Dong Q, Giorgianni F, Deng X, Beranova-Giorgianni S, Bridges D, Park EA, et al.: Phosphorylation of Sterol Regulatory Element Binding Protein-1a by Protein Kinase A (PKA) Regulates Transcriptional Activity. Biochemical and Biophysical Research Communications 2014, 449: 449-454.

[87] Roqueta-Rivera M, Esquejo RM, Phelan PE, Sandor K, Daniel B, Foufelle F, et al.: SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation. Cell Metabolism 2016, 24: 474-484.

[88] Takeuchi Y, Murayama Y, Aita Y, Mehrazad Saber Z, Karkoutly S, Tao D, et al.: GR-KLF15 Pathway Controls Hepatic Lipogenesis During Fasting. FEBS J 2024, 291: 259-271.

[89] Takeuchi Y, Yahagi N, Aita Y, Murayama Y, Sawada Y, Piao X, et al.: KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting. Cell Reports 2016, 16: 2373-2386.

[90] Romani P, Brian I, Santinon G, Pocaterra A, Audano M, Pedretti S, et al.: Extracellular Matrix Mechanical Cues Regulate Lipid Metabolism through Lipin-1 and SREBP. Nature Cell Biology 2019, 21: 338-347.

[91] Kondo A, Yamamoto S, Nakaki R, Shimamura T, Hamakubo T, Sakai J, et al.: Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote Tumor Progression. Cell Reports 2017, 18: 2228-2242.

[92] Horton JD, Goldstein JL, Brown MS: SREBPs: Activators of the Complete Program of Cholesterol and Fatty Acid Synthesis in the Liver. The Journal of Clinical Investigation 2002, 109: 1125-1131.

[93] Shimano H, Sato R: SREBP-regulated Lipid Metabolism: Convergent Physiology - Divergent Pathophysiology. Nature Reviews. Endocrinology 2017, 13: 710-730.

[94] Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, et al.: Crucial Step in Cholesterol Homeostasis: Sterols Promote Binding of SCAP to INSIG-1, a Membrane Protein that Facilitates Retention of SREBPs in ER. Cell 2002, 110: 489-500.

[95] Sun LP, Seemann J, Goldstein JL, Brown MS: Sterol-regulated Rransport of SREBPs from Endoplasmic Reticulum to Golgi: Insig Renders Sorting Signal in Scap Inaccessible to COPII Proteins. Proceedings of the National Academy of Sciences of the United States of America 2007, 104: 6519-6526.

[96] Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL: Direct Binding of Cholesterol to the Purified Membrane Region of SCAP: Mechanism for a Sterol-sensing Domain. Molecular Cell 2004, 15: 259-268.

[97] Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, Mangelsdorf DJ: Regulation of ATP-binding Cassette Sterol Transporters ABCG5 and ABCG8 by the Liver X Receptors Alpha and Beta. The Journal of Biological Chemistry 2002, 277: 18793-18800.

[98] Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, et al.: Role of LXRs in Control of Lipogenesis. Genes & Development 2000, 14: 2831-2838.

[99] Maxfield FR, Tabas I: Role of Cholesterol and Lipid Organization in Disease. Nature 2005, 438: 612-621.

[100] Postic C, Girard J: The Role of the Lipogenic Pathway in the Development of Hepatic Steatosis. Diabetes & Metabolism 2008, 34: 643-648.

[101] Soyal SM, Nofziger C, Dossena S, Paulmichl M, Patsch W: Targeting SREBPs for Treatment of the Metabolic Syndrome. Trends in Pharmacological Sciences 2015, 36: 406-416.

[102] Brown MS, Goldstein JL: Selective Versus Total Insulin Resistance: A Pathogenic Paradox. Cell Metabolism 2008, 7: 95-96.

[103] Ide T, Shimano H, Yahagi N, Matsuzaka T, Nakakuki M, Yamamoto T, et al.: SREBPs Suppress IRS-2-mediated Insulin Signalling in the Liver. Nature Cell Biology 2004, 6: 351-357.

[104] Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, et al.: Insulin-regulated Hepatic Gluconeogenesis through FOXO1-PGC-1alpha Interaction. Nature 2003, 423: 550-555.

[105] Patsch JR, Prasad S, Gotto AM Jr, Patsch W: High Density Lipoprotein2. Relationship of the Plasma Levels of this Lipoprotein Species to its Composition, to the Magnitude of Postprandial Lipemia, and to the Activities of Lipoprotein Lipase and Hepatic Lipase. The Journal of Clinical Investigation 1987, 80: 341-347.

[106] Nakagawa Y, Wang Y, Han SI, Okuda K, Oishi A, Yagishita Y, et al.: Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition. Cellular and Molecular Gastroenterology and Hepatology 2021, 11: 949-971.

[107] Bugianesi E, Petta S: NAFLD/NASH. Journal of Hepatology 2022, 77: 549-550.

[108] Loomba R, Friedman SL, Shulman GI: Mechanisms and Disease Consequences of Nonalcoholic Fatty Liver Disease. Cell 2021, 184: 2537-2564.

[109] Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, and Parks EJ: Sources of Fatty Acids Stored in Liver and Secreted Via Lipoproteins in Patients with Nonalcoholic Fatty Liver Disease. J Clin Invest 2005, 115: 1343-1351.

[110] Wu H, Ng R, Chen X, Steer CJ, Song G: MicroRNA-21 is a Potential Link between Non-alcoholic Fatty Liver Disease and Hepatocellular Carcinoma via Modulation of the HBP1-p53-Srebp1c Pathway. Gut 2016, 65: 1850-1860.

[111] Keam SJ: Resmetirom: First Approval. Drugs 2024, 84: 729-735.

[112] Hwang J, Hwang H, Shin H, Kim BH, Kang SH, Yoo JJ, et al.: Bariatric Intervention Improves Metabolic Dysfunction-associated Steatohepatitis in Patients with Obesity: A Systematic Review and Meta-Analysis. Clinical and Molecular Hepatology 2024, 30: 561-576.

[113] Ahmad E, Lim S, Lamptey R, Webb DR, Davies MJ: Type 2 Diabetes. Lancet 2022, 400: 1803-1820.

[114] Schwartz SS, Epstein S, Corkey BE, Grant SF, Gavin JR 3rd, Aguilar RB: The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell-Centric Classification Schema. Diabetes Care 2016, 39: 179-186.

[115] Wei F, Gu Y, He L, Kapoor A, Lin X, Dong Y, et al.: HSD17B6 Delays Type 2 Diabetes Development via Inhibiting SREBP Activation. Metabolism 2023, 145: 155631.

[116] Mayer AE, Löffler MC, Loza Valdés AE, Schmitz W, El-Merahbi R, Viera JT, et al.: The Kinase PKD3 Provides Negative Feedback on Cholesterol and Triglyceride Synthesis by Suppressing Insulin Signaling. Science Signaling 2019, eaav9150.

[117] Jie Z, Xie Z, Xu W, Zhao X, Jin G, Sun X, et al.: SREBP-2 Aggravates Breast Cancer Associated Osteolysis by Promoting Osteoclastogenesis and Breast Cancer Metastasis. Biochimica et biophysica acta. Molecular Basis of Disease 2019, 1865: 115-125.

[118] Zheng ZG, Zhang X, Zhou YP, Lu C, Thu PM, Qian C, et al.: Anhydroicaritin, a SREBPs Inhibitor, Inhibits RANKL-induced Osteoclastic Differentiation and Improves Diabetic Osteoporosis in STZ-induced Mice. European Journal of Pharmacology 2017, 809: 156-162.

[119] Zheng ZG, Cheng HM, Zhou YP, Zhu ST, Thu PM, Li HJ, et al.: Dual Targeting of SREBP2 and ERRα by Carnosic acid Suppresses RANKL-mediated Osteoclastogenesis and Prevents Ovariectomy-induced Bone Loss. Cell Death and Differentiation 2020, 27: 2048-2065.

[120] Xue L, Qi H, Zhang H, Ding L, Huang Q, Zhao D, et al.: Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy. Frontiers in Oncology 2020, 10: 1510.

[121] Bao J, Zhu L, Zhu Q, Su J, Liu M, Huang W: SREBP-1 is an Independent Prognostic Marker and Promotes Invasion and Migration in Breast Cancer. Oncology Letters 2016, 12: 2409-2416.

[122] Zhu Z, Zhao X, Zhao L, Yang H, Liu L, Li J, et al.: p54(nrb)/NONO Regulates Lipid Metabolism and Breast Cancer Growth through SREBP-1A. Oncogene 2016, 35: 1399-1410.

[123] Zhao Z, Hao D, Wang L, Li J, Meng Y, Li P, et al.: CtBP Promotes Metastasis of Breast Cancer through Repressing Cholesterol and Activating TGF-beta Signaling. Oncogene 2019, 38: 2076-2091.

[124] Gao Y, Zhao Q, Mu X, Zhu H, Liu B, Yao B, et al.: SREBP1 Promotes 5-FU Resistance in Colorectal Cancer Cells by Inhibiting the Expression of Caspase7. International Journal of Clinical and Experimental Pathology 2019, 12: 1095-1100.

[125] Gao Y, Nan X, Shi X, Mu X, Liu B, Zhu H, et al.: SREBP1 Promotes the Invasion of Colorectal Cancer Accompanied Upregulation of MMP7 Expression and NF-κB Pathway Activation. BMC Cancer 2019, 19: 685.

[126] Wang H, Chen Y, Liu Y, Li Q, Luo J, Wang L, et al.: The lncRNA ZFAS1 Regulates Lipogenesis in Colorectal Cancer by Binding Polyadenylate-binding Protein 2 to Stabilize SREBP1 mRNA. Molecular Therapy. Nucleic Acids 2022, 27: 363-374.

[127] Li C, Yang W, Zhang J, Zheng X, Yao Y, Tu K, et al.: SREBP-1 has a Prognostic Role and Contributes to Invasion and Metastasis in Human Hepatocellular Carcinoma. International Journal of Molecular Sciences 2014, 15: 7124-7138.

[128] Kumar DP, Santhekadur PK, Seneshaw M, Mirshahi F, Uram-Tuculescu C, Sanyal AJ: A Regulatory Role of Apoptosis Antagonizing Transcription Factor in the Pathogenesis of Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma. Hepatology 2019, 69: 1520-1534.

[129] Chen J, Ding C, Chen Y, Hu W, Yu C, Peng C, et al.: ACSL4 Reprograms Fatty Acid Metabolism in Hepatocellular Carcinoma via c-Myc/SREBP1 Pathway. Cancer Letters 2021, 502: 154-165.

[130] Yu X, Lin Q, Wu Z, Zhang Y, Wang T, Zhao S, et al.: ZHX2 Inhibits SREBP1c-mediated De Novo Lipogenesis in Hepatocellular Carcinoma via miR-24-3p. The Journal of Pathology 2020, 252: 358-370.

[131] Heo MJ, Kang SH, Kim YS, Lee JM, Yu J, Kim HR, et al.: UBC12-mediated SREBP-1 Neddylation Worsens Metastatic Tumor Prognosis. International Journal of Cancer 2020, 147: 2550-2563.

[132] Moon SH, Huang CH, Houlihan SL, Regunath K, Freed-Pastor WA, Morris JP 4th: p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression. Cell 2019, 176: 564-580.e519.

[133] Ettinger SL, Sobel R, Whitmore TG, Akbari M, Bradley DR, Gleave ME, et al.: Dysregulation of Sterol Response Element-binding Proteins and Downstream Effectors in Prostate Cancer During Progression to Androgen Independence. Cancer Research 2004, 64: 2212-2221.

[134] Suh JH, Gong EY, Kim JB, Lee IK, Choi HS, Lee K: Sterol Regulatory Element-binding Protein-1c Represses the Transactivation of Androgen Receptor and Androgen-dependent Growth of Prostatic Cells. Molecular Cancer Research 2008, 6: 314-324.

[135] Audet-Walsh É, Vernier M, Yee T, Laflamme C, Li S, Chen Y, et al.: SREBF1 Activity Is Regulated by an AR/mTOR Nuclear Axis in Prostate Cancer. Molecular Cancer Research 2018, 16: 1396-1405.

[136] Kanagasabai T, Li G, Shen TH, Gladoun N, Castillo-Martin M, Celada SI, et al.: MicroRNA-21 Deficiency Suppresses Prostate Cancer Progression through Downregulation of the IRS1-SREBP-1 Signaling Pathway. Cancer Letters 2022, 525: 46-54.

[137] Yang M, Liu W, Pellicane C, Sahyoun C, Joseph BK, Gallo-Ebert C, et al.: Identification of miR-185 as a Regulator of De Novo Cholesterol Biosynthesis and Low Density Lipoprotein Uptake. Journal of Lipid Research 2014, 55: 226-238.

[138] Li X, Chen YT, Josson S, Mukhopadhyay NK, Kim J, Freeman MR, et al.: MicroRNA-185 and 342 Inhibit Tumorigenicity and Induce Apoptosis through Blockade of the SREBP Metabolic Pathway in Prostate Cancer Cells. PLoS One 2013, 8: e70987.

[139] Zhao L, Peng Y, He S, Li R, Wang Z, Huang J, et al.: Apatinib Induced Ferroptosis by Lipid Peroxidation in Gastric Cancer. Gastric Cancer: Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2021, 24: 642-654.

[140] Guo D, Prins RM, Dang J, Kuga D, Iwanami A, Soto H, et al.: EGFR Signaling through an Akt-SREBP-1-Dependent, Rapamycin-resistant Pathway Sensitizes Glioblastomas to Antilipogenic Therapy. Science Signaling 2009, 2: ra82.

[141] Choi Y, Kawazoe Y, Murakami K, Misawa H, Uesugi M: Identification of Bioactive Molecules by Adipogenesis Profiling of Organic Compounds. The Journal of Biological Chemistry 2003, 278: 7320-7324.

[142] Kamisuki S, Shirakawa T, Kugimiya A, Abu-Elheiga L, Choo HY, Yamada K, et al.: Synthesis and Evaluation of Diarylthiazole Derivatives that Inhibit Activation of Sterol Regulatory Element-Binding Proteins. Journal of Medicinal Chemistry 2011, 54: 4923-4927.

[143] Peng Z, Chen L, Wang M, Yue X, Wei H, Xu F, et al.: SREBP Inhibitors: An Updated Patent Review for 2008-present. Expert Opinion on Therapeutic Patents 2023, 33: 669-680.

[144] Zhao X, Xiaoli, Zong H, Abdulla A, Yang ES, Wang Q, et al.: Inhibition of SREBP Transcriptional Activity by a Boron-containing Compound Improves Lipid Homeostasis in Diet-induced Obesity. Diabetes 2014, 63: 2464-2473.

[145] Yuan S, Chu H, Chan JF, Ye ZW, Wen L, Yan B, et al.: SREBP-dependent Lipidomic Reprogramming as a Broad-spectrum Antiviral Target. Nature Communications 2019, 10: 120.

[146] Zhang J, Zhang LN, Chen DM, Fu YY, Zhang F, Yang LL, et al.: 2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic Acid Ameliorates Metabolic Disorders in High-fat diet-fed Mice. Acta Pharmacologica Sinica 2015, 36: 483-496.

[147] Park EJ, Kim YM, Kim HJ, Jang SY, Oh MH, Lee DH, et al.: (S)YS-51, a Novel Isoquinoline Alkaloid, Attenuates Obesity-associated Non-alcoholic Fatty Liver Disease in Mice by Suppressing Lipogenesis, Inflammation and Coagulation. European Journal of Pharmacology 2016, 788: 200-209.

[148] Xu S, Smothers JC, Rye D, Endapally S, Chen H, Li S, et al.: A Cholesterol-binding Bacterial Toxin Provides a Strategy for Identifying a Specific Scap Inhibitor that Blocks Lipid Synthesis in Animal Cells. Proceedings of the National Academy of Sciences of the United States of America 2024, 121: e2318024121.

[149] Wang TB, Geng M, Jin H, Tang AG, Sun H, Zhou LZ, et al.: SREBP1 Site 1 Protease Inhibitor PF-429242 Suppresses Renal Cell Carcinoma Cell Growth. Cell Death & Disease 2021, 12: 717.

[150] Guan M, Fousek K, Jiang C, Guo S, Synold T, Xi B, et al.: Nelfinavir Induces Liposarcoma Apoptosis through Inhibition of Regulated Intramembrane Proteolysis of SREBP-1 and ATF6. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2011, 17: 1796-1806.

[151] Xiao PT, Xie ZS, Kuang YJ, Liu SY, Zeng C, Li P, et al.: Discovery of a Potent FKBP38 Agonist that Ameliorates HFD-induced Hyperlipidemia via mTOR/P70S6K/SREBPs Pathway. Acta Pharmaceutica Sinica B 2021, 11: 3542-3552.

[152] Wang S, Sheng F, Zou L, Xiao J, Li P: Hyperoside Attenuates Non-alcoholic Fatty Liver Disease in Rats via Cholesterol Metabolism and Bile Acid Metabolism. Journal of Advanced Research 2021, 34: 109-122.

[153] Ding L, Li J, Song B, Xiao X, Zhang B, Qi M, et al.: Curcumin Rescues High Fat Diet-induced Obesity and Insulin Sensitivity in Mice through Regulating SREBP Pathway. Toxicology and Applied Pharmacology 2016, 304: 99-109.

[154] Miyata S, Inoue J, Shimizu M, Sato R: Xanthohumol Improves Diet-induced Obesity and Fatty Liver by Suppressing Sterol Regulatory Element-binding Protein (SREBP) Activation. The Journal of Biological Chemistry 2015, 290: 20565-20579.

[155] Zheng ZG, Zhang X, Liu XX, Jin XX, Dai L, Cheng HM, et al.: Inhibition of HSP90β Improves Lipid Disorders by Promoting Mature SREBPs Degradation via the Ubiquitin-proteasome System. Theranostics 2019, 9: 5769-5783.

[156] Lee JW, Choe SS, Jang H, Kim J, Jeong HW, Jo H, et al.: AMPK Activation with Glabridin Ameliorates Adiposity and Lipid Dysregulation in Obesity. Journal of Lipid Research 2012, 53: 1277-1286.

[157] Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al.: Resveratrol Improves Health and Survival of Mice on a High-calorie Diet. Nature 2006, 444: 337-342.

[158] Zhu X, Bian H, Wang L, Sun X, Xu X, Yan H, et al.: Berberine Attenuates Nonalcoholic Hepatic Steatosis through the AMPK-SREBP-1c-SCD1 Pathway. Free Radical Biology & Medicine 2019, 141: 192-204.

[159] Song CY, Shi J, Zeng X, Zhang Y, Xie WF, Chen YX .: Sophocarpine Alleviates Hepatocyte Steatosis through Activating AMPK Signaling Pathway. Toxicology In Vitro: An International Journal Published in Association with BIBRA 2013, 27: 1065-1071.

[160] Quan HY, Kim DY, Chung SH: Caffeine Attenuates Lipid Accumulation via Activation of AMP-activated Protein Kinase Signaling Pathway in HepG2 Cells. BMB Reports 2013, 46: 207-212.

[161] Varshney S, Shankar K, Beg M, Balaramnavar VM, Mishra SK, Jagdale P, et al.: Rohitukine Inhibits In Vitro Adipogenesis Arresting Mitotic Clonal Expansion and Improves Dyslipidemia In Vivo. Journal of Lipid Research 2014, 55: 1019-1032.

[162] Zheng ZG, Zhu ST, Cheng HM, Zhang X, Cheng G, Thu PM, et al.: Discovery of a Potent SCAP Degrader that Ameliorates HFD-induced Obesity, Hyperlipidemia and Insulin Resistance via an Autophagy-independent Lysosomal Pathway. Autophagy 2021, 17: 1592-1613.

[163] Zhang Y, Ren P, Kang Q, Liu W, Li S, Li P, et al.: Effect of Tetramethylpyrazine on Atherosclerosis and SCAP/SREBP-1c Signaling Pathway in ApoE(-/-) Mice Fed with a High-Fat Diet. Evidence-based Complementary and Alternative Medicine: eCAM 2017, 2017: 3121989.

[164] Ma W, Ding H, Gong X, Liu Z, Lin Y, Zhang Z, et al.: Methyl Protodioscin Increases ABCA1 Expression and Cholesterol Efflux while Inhibiting Gene Expressions for Synthesis of Cholesterol and Triglycerides by Suppressing SREBP Transcription and microRNA 33a/b Levels. Atherosclerosis 2015, 239: 566-570.

[165] Quan HY, Yuan HD, Jung MS, Ko SK, Park YG, Chung SH: Ginsenoside Re Lowers Blood Glucose and Lipid Levels via Activation of AMP-activated Protein Kinase in HepG2 Cells and High-fat Diet Fed Mice. International Journal of Molecular Medicine 2012, 29: 73-80.

[166] Wang C, Li Y, Hao M, Li W: Astragaloside IV Inhibits Triglyceride Accumulation in Insulin-Resistant HepG2 Cells via AMPK-Induced SREBP-1c Phosphorylation. Frontiers in Pharmacology 2018, 9: 345.

[167] Do MT, Kim HG, Choi JH, Khanal T, Park BH, Tran TP, et al.: Phillyrin Attenuates High Glucose-induced Lipid Accumulation in Human HepG2 Hepatocytes through the Activation of LKB1/AMP-activated Protein Kinase-dependent Signalling. Food Chemistry 2013, 136: 415-425.

[168] Lin Y, Zhao WR, Shi WT, Zhang J, Zhang KY, Ding Q, et al.: Pharmacological Activity, Pharmacokinetics, and Toxicity of Timosaponin AIII, a Natural Product Isolated From Anemarrhena asphodeloides Bunge: A Review . Frontiers in Pharmacology 2020, 11: 764.

[169] Bai T, Yang Y, Yao YL, Sun P, Lian LH, Wu YL, et al.: Betulin Alleviated Ethanol-induced Alcoholic Liver Injury via SIRT1/AMPK Signaling Pathway. Pharmacological Research 2016, 105: 1-12.

[170] Zhang Y, Geng C, Liu X, Li M, Gao M, Liu X, et al.: Celastrol Ameliorates Liver Metabolic Damage Caused by a High-fat Diet through Sirt1. Molecular Metabolism 2017, 6: 138-147.

[171] Zhong H, Chen K, Feng M, Shao W, Wu J, Chen K, et al.: Genipin Alleviates High-fat diet-induced Hyperlipidemia and Hepatic Lipid Accumulation in Mice via miR-142a-5p/SREBP-1c Axis. FEBS J 2018, 285: 501-517.

[172] Zheng ZG, Lu C, Thu PM, Zhang X, Li HJ, Li P, et al.: Correction: Praeruptorin B Improves Diet-induced Hyperlipidemia and Alleviates Insulin Resistance via Regulating SREBP Signaling Pathway. RSC Advances 2019, 9: 6101.

[173] Ding L, Li J, Song B, Xiao X, Huang W, Zhang B, et al.: Andrographolide Prevents High-fat diet-induced Obesity in C57BL/6 Mice by Suppressing the Sterol Regulatory Element-binding Protein Pathway. The Journal of Pharmacology and Experimental Therapeutics 2014, 351: 474-483.

[174] Chen J, Yue J, Liu J, Liu Y, Jiao KL, Teng MY, et al.: Salvianolic Acids Improve Liver Lipid Metabolism in Ovariectomized Rats via Blocking STAT-3/SREBP1 Signaling. Chinese Journal of Natural Medicines 2018, 16: 838-845.

[175] Miyata S, Inoue J, Shimizu M, Sato R: Allyl Isothiocyanate Suppresses the Proteolytic Activation of Sterol Regulatory Element-binding Proteins and De Novo Fatty Acid and Cholesterol Synthesis. Bioscience, Biotechnology, and Biochemistry 2016, 80: 1006-1011.

[176] Meng H, Shen M, Li J, Zhang R, Li X, Zhao L, et al.: Novel SREBP1 Inhibitor Cinobufotalin Suppresses Proliferation of Hepatocellular Carcinoma by Targeting Lipogenesis. European Journal of Pharmacology 2021, 906: 174280.

[177] Repa JJ, Mangelsdorf DJ: The Role of Orphan Nuclear Receptors in the Regulation of Cholesterol Homeostasis. Annual Review of Cell and Developmental Biology 2000, 16: 459-481.

[178] Jiang SY, Yang X, Yang Z, Li JW, Xu MQ, Qu YX, et al.: Discovery of an Insulin-induced Gene Binding Compound that Ameliorates Nonalcoholic Steatohepatitis by Inhibiting Sterol Regulatory Element-binding Protein-mediated Lipogenesis. Hepatology 2022, 76: 1466-1481.

[179] Asano L, Watanabe M, Ryoden Y, Usuda K, Yamaguchi T, Khambu B, et al.: Vitamin D Metabolite, 25-Hydroxyvitamin D, Regulates Lipid Metabolism by Inducing Degradation of SREBP/SCAP. Cell Chemical Biology 2017, 24: 207-217.

[180] Kawagoe F, Mendoza A, Hayata Y, Asano L, Kotake K, Mototani S, et al.: Discovery of a Vitamin D Receptor-Silent Vitamin D Derivative That Impairs Sterol Regulatory Element-Binding Protein In Vivo. Journal of Medicinal Chemistry 2021, 64: 5689-5709.

[181] Esquejo RM, Roqueta-Rivera M, Shao W, Phelan PE, Seneviratne U, Am Ende CW, et al.: Dipyridamole Inhibits Lipogenic Gene Expression by Retaining SCAP-SREBP in the Endoplasmic Reticulum. Cell Chemical Biology 2021, 28: 169-179.e167.

[182] Shao W, Machamer CE and Espenshade PJ: Fatostatin Blocks ER Exit of SCAP but Inhibits Cell Growth in a SCAP-independent Manner. Journal of Lipid Research 2016, 57: 1564-1573.

[183] Gholkar AA, Cheung K, Williams KJ, Lo YC, Hamideh SA, Nnebe C, et al.: Fatostatin Inhibits Cancer Cell Proliferation by Affecting Mitotic Microtubule Spindle Assembly and Cell Division. The Journal of Biological Chemistry 2016, 291: 17001-17008.

[184] Wang Q, Hu R, Li W, Tai Y, Gu W, Das BC, et al.: BF175 Inhibits Endometrial Carcinoma through SREBP-regulated Metabolic Pathways In Vitro. Molecular and Cellular Endocrinology 2021, 523: 111135.

[185] Párraga A, Bellsolell L, Ferré-D’amaré AR, Burley SK: Co-crystal Structure of Sterol Regulatory Element Binding Protein 1a at 2.3 A Resolution. Structure 1998, 6: 661-672.

[186] Nagula RL, Wairkar S: Recent Advances in Topical Delivery of Flavonoids: A Review. Journal of Controlled Release: Official Journal of the Controlled Release Society 2019, 296: 190-201.

[187] Lin X, Zhang J, Chu Y, Nie Q, Zhang J: Berberine Prevents NAFLD and HCC by Modulating Metabolic Disorders. Pharmacology & Therapeutics 2024, 254: 108593.

[188] Liu Y, Hua W, Li Y, Xian X, Zhao Z, Liu C, et al.: Berberine Suppresses Colon Cancer Cell Proliferation by Inhibiting the SCAP/SREBP-1 Signaling Pathway-mediated Lipogenesis. Biochemical Pharmacology 2020, 174: 113776.

[189] Zhu W, Hong Y, Tong Z, He X, Li Y, Wang H, et al.: Activation of Hepatic Adenosine A1 Receptor Ameliorates MASH via Inhibiting SREBPs Maturation. Cell Reports. Medicine 2024, 5: 101477.

[190] Tang JJ, Li JG, Qi W, Qiu WW, Li PS, Li BL, et al.: Inhibition of SREBP by a Small Molecule, Betulin, Improves Hyperlipidemia and Insulin Resistance and Reduces Atherosclerotic Plaques. Cell Metabolism 2021, 33: 222.

[191] Yin F, Feng F, Wang L, Wang X, Li Z, Cao Y: SREBP-1 Inhibitor Betulin Enhances the Antitumor Effect of Sorafenib on Hepatocellular Carcinoma via Restricting Cellular Glycolytic Activity. Cell Death & Disease 2019, 10: 672.

[192] Ren S, Hylemon PB, Marques D, Gurley E, Bodhan P, Hall E, et al.: Overexpression of Cholesterol Transporter StAR Increases In Vivo Rates of Bile Acid Synthesis in the Rat and Mouse. Hepatology 2004, 40: 910-917.

[193] Ishida CT, Kubota CS, Carlyle E, Tsukamoto T, Espenshade PJ: A High-Throughput Screening Platform Identifies FDA-Approved Drugs That Inhibit SREBP Pathway Activation. ACS Chemical Biology 2024, 19: 1695-1704.

[194] Singaravelu R, Quan C, Powdrill MH, Shaw TA, Srinivasan P, Lyn RK, et al.: MicroRNA-7 Mediates Cross-talk between Metabolic Signaling Pathways in the Liver. Science Reports 2018, 8: 361.

[195] Rayner KJ, Suárez Y, Dávalos A, Parathath S, Fitzgerald ML, Tamehiro N, et al.: MiR-33 Contributes to the Regulation of Cholesterol Homeostasis. Science 2010, 328: 1570-1573.

[196] Jeon TI, Esquejo RM, Roqueta-Rivera M, Phelan PE, Moon YA, Govindarajan SS, et al.: An SREBP-responsive microRNA Operon Contributes to a Regulatory Loop for Intracellular Lipid Homeostasis. Cell Metabolism 2013, 18: 51-61.

[197] Satoshi K, Yuki M, Shigeyuki K, Tange M, Fujiwara N, Hayata Y, et al.: Inhibiting SCAP/SREBP Exacerbates Liver Injury and Carcinogenesis in Murine Nonalcoholic Steatohepatitis. The Journal of Clinical Investigation 2022, 132: e151895.