New developments in the biology of fibroblast growth factors

WIREs Mechanisms of Disease, Journal Year: 2022, Volume and Issue: 14(4)

Published: Feb. 9, 2022

Abstract The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting canonical FGFs and endocrine that activate four receptor tyrosine kinases (FGFRs 1–4) intracellular (intracellular or iFGFs) primarily function to regulate the activity voltage‐gated sodium channels other molecules. FGFs, iFGFs have been reviewed extensively by us others. In this review, we briefly summarize past reviews then focus on new developments in FGF field since our last review 2015. Some highlights 6 years include use optogenetic tools, viral vectors, inducible transgenes experimentally modulate signaling, clinical small molecule FGFR inhibitors, an expanded understanding functions for stem cell pluripotency differentiation, roles tissue homeostasis regeneration, a continuing elaboration mechanisms development, expanding appreciation neuropsychiatric diseases. This article categorized under: Cardiovascular Diseases > Molecular Cellular Physiology Neurological Congenital Stem Cells Development Cancer

Language: Английский

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Aging-suppressor Klotho: Prospects in diagnostics and therapeutics

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 82, P. 101766 - 101766

Published: Oct. 22, 2022

The protein Klotho (KL) was first discovered in KL-deficient mice, which developed a syndrome similar to premature aging humans. Since then, KL has been implicated multiple molecular signaling pathways and diseases. shown have anti-aging, healthspan lifespan extending, cognitive enhancing, anti-oxidative, anti-inflammatory, anti-tumor properties. levels decrease with age many Therefore, it of great interest develop KL-boosting or restoring drug, supplement endogenous exogenous genetic material recombinant protein, use the body as marker for efficacy such drugs biomarker diagnosis management goal this study provide comprehensive review across groups individuals who are healthy certain health conditions, using four sources: blood, cerebrospinal fluid, urine, whole biopsy/necropsy tissue. By doing so, baseline can be identified lifespan, absence presence disease. In turn, these findings used guide development future KL-based therapeutics biomarkers, will heavily rely on an individual's range efficacious. A total 65 studies were collected primarily PubMed database. Research articles that published up April 2022 included. Statistical analysis conducted RStudio. Mean median blood individuals, mean renal metabolic endocrine conditions age. Similarly, CSF patients AD also declined compared age-matched controls. present confirms trend humans, among those healthy, even further endocrine/metabolic illnesses. Further, by drawing from works, we able general idea ranges, specifically populations. These data add current knowledge normal how they change time disease, potentially support efforts create treatments screening tools better manage aging, renal, metabolic/endocrine

Language: Английский

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Klotho, Oxidative Stress, and Mitochondrial Damage in Kidney Disease

Antioxidants, Journal Year: 2023, Volume and Issue: 12(2), P. 239 - 239

Published: Jan. 20, 2023

Reducing oxidative stress stands at the center of a prevention and control strategy for mitigating cellular senescence aging. Kidney disease is characterized by premature aging syndrome, to find modulator targeting against stress, mitochondrial dysfunction, in kidney cells could be great significance prevent progression this disease. This review focuses on pathogenic mechanisms related appearance damage dysfunction In scenario, anti-aging Klotho protein plays crucial role modulating signaling pathways involving manganese-containing superoxide dismutase (Mn-SOD) transcription factors FoxO Nrf2, known antioxidant systems, other function regulators, such as uncoupling 1 (UCP1), B-cell lymphoma-2 (BCL-2), Wnt/β-catenin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), factor EB, (TFEB), (PPAR-gamma). Therefore, postulated very promising new target future therapeutic strategies mitochondria abnormalities, patients.

Language: Английский

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Structural basis for FGF hormone signalling

Nature, Journal Year: 2023, Volume and Issue: 618(7966), P. 862 - 870

Published: June 7, 2023

α/βKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23)1,2 their cognate cell-surface FGF receptors (FGFR1-4) thereby stabilizing the endocrine FGF-FGFR complex3-6. However, these still require heparan sulfate (HS) proteoglycan as an additional coreceptor to induce FGFR dimerization/activation hence elicit essential metabolic activities6. To reveal molecular mechanism underpinning role of HS, we solved cryo-electron microscopy structures three distinct 1:2:1:1 FGF23-FGFR-αKlotho-HS quaternary complexes featuring 'c' splice isoforms FGFR1 (FGFR1c), FGFR3 (FGFR3c) or FGFR4 receptor component. These structures, supported by cell-based complementation heterodimerization experiments, that a single HS chain enables FGF23 its primary within 1:1:1 FGF23-FGFR-αKlotho ternary complex jointly recruit lone secondary molecule leading asymmetric dimerization activation. αKlotho does not directly participate in recruiting receptor/dimerization. We also show mode is applicable paracrine FGFs signal solely HS-dependent fashion. Our structural biochemical data overturn current symmetric paradigm provide blueprints for rational discovery modulators signalling2 therapeutics human diseases cancer.

Language: Английский

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Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies

Pharmacological Reviews, Journal Year: 2023, Volume and Issue: 75(4), P. 675 - 713

Published: Feb. 2, 2023

An increase in life expectancy developed countries has led to a surge of chronic aging-related diseases. In the last few decades, several studies have provided evidence prominent role cellular senescence many these pathologies. Key traits senescent cells include cell cycle arrest, apoptosis resistance, and secretome shift senescence-associated secretory phenotype resulting increased secretion various intermediate bioactive factors important for pathophysiology. However, is highly phenotypically heterogeneous process, hindering discovery totally specific accurate biomarkers. Also, strategies prevent pathologic effect accumulation during aging by impairing onset or promoting clearance shown great potential vivo studies, some are already early stages clinical translation. The adaptability senotherapeutic approaches human application been questioned due lack proper targeting involvement physiologic functions. this review, we explore its influence on expression biomarkers currently used detection. We also discuss current regarding efficacy, reliability, development stage, applicability main existing strategies.

Significance Statement

This paper an extensive review what known about complex process explores most defining features. body discussion focuses how multifeature fluctuation physiological both caused limitation search truly reliable progression senotherapies.

Language: Английский

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Klotho alleviates contrast-induced acute kidney injury by suppressing oxidative stress, inflammation, and NF-KappaB/NLRP3-mediated pyroptosis

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 118, P. 110105 - 110105

Published: April 3, 2023

Language: Английский

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Regulation of FGF23 production and phosphate metabolism by bone–kidney interactions

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 19(3), P. 185 - 193

Published: Jan. 9, 2023

Language: Английский

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Serum protein α-klotho mediates the association between lead, mercury, and kidney function in middle-aged and elderly populations

Environmental Health and Preventive Medicine, Journal Year: 2025, Volume and Issue: 30(0), P. 10 - 10

Published: Jan. 1, 2025

Heavy metals are significant risk factors for kidney function. Numerous studies have shown that exposure to heavy negatively correlates with function through oxidative stress pathways, and serum α-klotho is linked stress. However, the role of in relationship between blood lead, mercury, remains unclear. This study evaluated mediating alpha-klotho mercury renal function, using data from 2007-2016 National Health Nutrition Examination Survey (NHANES) U.S. adults aged 40-79. The sample included 11,032 participants, α-klotho, other relevant covariates measured. Inductively coupled plasma mass spectrometry was used assess lead levels, enzyme-linked immunosorbent assay (ELISA) employed measure α-klotho. Kidney estimated glomerular filtration rate (eGFR) based on creatinine levels. Multivariable linear regression conducted analyze relationships eGFR. A mediation analysis model whether influenced these associations. We observed a association Mediation revealed accounted 12.76% eGFR NHANES population. Subgroup showed mediated 12.43%, 6.87%, 21.50% 5.44% women, middle-aged (40-59 years old), without cardiovascular disease hypertension, respectively. did not mediate terms gender or age. newly identified pathway may provide valuable insights prevention treatment mechanisms related impairment. found associated According results subgroup analysis, females, middle 60-79 years. clinically significant, α-Klotho clinical significance.

Language: Английский

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The role of endothelin receptor antagonists in kidney disease

Renal Failure, Journal Year: 2025, Volume and Issue: 47(1)

Published: Feb. 27, 2025

Kidney diseases are among the most prevalent conditions worldwide, impacting over 850 million individuals. They categorized into acute kidney injury and chronic disease. Current preclinical clinical trials have demonstrated that endothelin (ET) is linked to onset progression of In diseases, pathological such as hyperglycemia, acidosis, insulin resistance, elevated angiotensin II levels lead an increase in ET. This elevation activates receptor type A, resulting harmful effects like proteinuria a reduced glomerular filtration rate (GFR). Therefore, slow disease, antagonists (ERAs) been proposed promising new therapies. Numerous studies efficacy ERAs significantly reducing improving GFR, thereby slowing diseases. review discusses mechanisms action treating their safety studies, explores future prospects for ERAs.

Language: Английский

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Metabolic Targets in Nonalcoholic Fatty Liver Disease

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2019, Volume and Issue: 8(2), P. 247 - 267

Published: Jan. 1, 2019

The prevalence and diagnosis of nonalcoholic fatty liver disease (NAFLD) is on the rise worldwide currently has no FDA-approved pharmacotherapy. increase in burden NAFLD a more severe form this progressive disease, steatohepatitis (NASH), largely mirrors obesity type 2 diabetes (T2D) reflects hepatic manifestation an altered metabolic state. Indeed, syndrome, defined as constellation obesity, insulin resistance, hyperglycemia, dyslipidemia hypertension, major risk factor predisposing NASH. There are multiple potential pharmacologic strategies to rebalance aspects disordered metabolism NAFLD. These include therapies aimed at reducing steatosis by directly modulating lipid within liver, inhibiting fructose metabolism, altering delivery free acids from adipose targeting resistance and/or glycemia, pleiotropic pathways simultaneously. Emerging data human genetics also supports role for drivers progression In review, we highlight prominent pathogenesis discuss targets NASH SummaryThis review highlights gives current overview treatment landscape steatohepatitis. This Nonalcoholic conditions that originates with excess accumulation fat (defined >5%). (NASH) clinical histological subset associated increased all-cause mortality, cirrhosis end-stage cardiovascular incidence both liver-related non–liver-related cancers.1Sanyal A.J. Friedman S.L. McCullough Dimick-Santos L. American Association Study Liver D, United States F, Drug A. Challenges opportunities drug biomarker development steatohepatitis: findings recommendations Diseases-U.S. Food Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (0) Google Scholar diagnosed clinically biopsy demonstrating steatosis, inflammation, cytological ballooning hepatocytes, often varying degrees fibrosis. progresses increasing fibrosis, developing patients,1Sanyal most common complication being hepatocellular carcinoma.2Khan F.Z. Perumpail R.B. Wong R.J. Ahmed Advances carcinoma: steatohepatitis-related carcinoma.World J Hepatol. 7: 2155-2161Crossref (30) Metabolic perturbations, including impaired glycemic control, have been hypothesized contribute molecular (Figure 1). Steatosis necessary but not sufficient component NASH.3Day C.P. James O.F. Hepatic steatosis: innocent bystander or guilty party?.Hepatology. 1998; 27: 1463-1466Crossref (329) Consistent this, studies demonstrated severity predicts concomitant well cirrhosis.4Reeves H.L. Burt A.D. Wood S. Day stellate cell activation occurs absence hepatitis alcoholic correlates steatosis.J 1996; 25: 677-683Abstract Full Text PDF Scholar, 5Sorensen T.I. Orholm M. Bentsen K.D. Hoybye G. Eghoje K. Christoffersen P. Prospective evaluation alcohol abuse injury men predictors cirrhosis.Lancet. 1984; 2: 241-244Abstract (297) 6Wanless I.R. Lentz J.S. Fatty (steatohepatitis) obesity: autopsy study analysis factors.Hepatology. 1990; 12: 1106-1110Crossref (1002) Genetic polymorphisms humans, I148M polymorphism PNPLA3 gene, shown turn NASH.7Romeo Kozlitina J. Xing C. Pertsemlidis Cox D. Pennacchio L.A. Boerwinkle E. Cohen J.C. Hobbs H.H. variation confers susceptibility disease.Nat Genet. 2008; 40: 1461-1465Crossref (1500) 8Rotman Y. Koh Zmuda J.M. Kleiner D.E. Liang T.J. Nash C.R.N. association genetic variability patatin-like phospholipase domain-containing protein 3 (PNPLA3) disease.Hepatology. 2010; 52: 894-903Crossref (284) observations taken together provide evidence key pathogenic consequence imbalance triglyceride (TG) production uptake into clearance removal 1).9Cohen Horton J.D. Human disease: old questions new insights.Science. 2011; 332: 1519-1523Crossref (1167) Elevated body mass index significant steatosis10Browning Szczepaniak L.S. Dobbins R. Nuremberg Grundy S.M. Prevalence urban population States: impact ethnicity.Hepatology. 2004; 1387-1395Crossref (2488) suggesting caloric intake Altering balance TG either (or both) promoting likewise expected reduce steatosis. Amelioration buildup lipotoxic species, suppress subsequently fibrogenesis animal models modalities which result downstream improvements inflammation fibrosis.11Honda Imajo Kato T. Kessoku Ogawa Tomeno W. Mawatari H. Fujita Yoneda Saito Nakajima selective SGLT2 inhibitor ipragliflozin therapeutic effect mice.PLoS One. 2016; 11: e0146337Crossref (23) 12Ji Wang Deng Li X. Jiang Z. Resveratrol ameliorates methionine/choline-deficient diet-induced through regulating autophagy.Lipids Health Dis. 14: 134Crossref (32) 13Kita Takamura Misu Ota Kurita Takeshita Uno Matsuzawa-Nagata N. Ando Fujimura Hayashi Kimura Ni Otoda Miyamoto Zen Nakanuma Kaneko Metformin prevents reverses non-diabetic mouse model steatohepatitis.PLoS 2012; e43056Crossref (74) 14Klein Fujii Sandel Shibazaki Wakamatsu Mark Yoneyama Linagliptin alleviates non-alcoholic steatohepatitis.Med Mol Morphol. 2014; 47: 137-149Crossref (27) 15Liu Struik Nies V.J. Jurdzinski Harkema de Bruin Verkade H.J. Downes Evans R.M. van Zutphen Jonker J.W. Effective fibroblast growth 1 disease.Proc Natl Acad Sci U S 113: 2288-2293Crossref 16Morrison M.C. Mulder Verschuren Pieterman Toet Heeringa Wielinga P.Y. Kooistra Kleemann Mirtoselect, anthocyanin-rich bilberry extract, attenuates fibrosis ApoE( *)3Leiden mice.J 62: 1180-1186Abstract 17Qiang Xu Zhang Zhao Chen Liu Demethyleneberberine AMPK inhibition oxidative stress.Biochem Biophys Res Commun. 472: 603-609Crossref (22) 18Soares e Silva A.K. Oliveira Cipriano Torres dos Santos Gomes F.O. B. Lima Ribeiro Costa Mdo Pitta Ida Peixoto C.A. LPSF/GQ-02 inhibits (NAFLD).PLoS 10: e0123787Crossref (6) 19Staels Rubenstrunk Noel Rigou Delataille Millatt L.J. Baron Lucas Tailleux Hum D.W. Ratziu V. Cariou Hanf Hepatoprotective effects dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, rodent disease/nonalcoholic steatohepatitis.Hepatology. 2013; 58: 1941-1952Crossref (186) 20Verbeek Lannoo Pirinen Ryu Spincemaille Vander Elst I. Windmolders Thevissen Cammue B.P. Pelt Fransis Van Eyken Ceuterick-De Groote Veldhoven P.P. Bedossa Nevens F. Auwerx Cassiman Roux-en-y gastric bypass mitochondrial dysfunction mice steatohepatitis.Gut. 64: 673-683Crossref (33) 21Wada Miyashita Sasaki Aruga Nakamura Ishii Sasahara Kanasaki Kitada Koya Shimano Tsuneki Sasaoka Eplerenone phenotypes syndrome liver-specific SREBP-1c Tg fed high-fat high-fructose diet.Am Physiol Endocrinol Metab. 305: E1415-E1425Crossref Perhaps compelling support comes bariatric surgery literature. Bariatric leads restoration energy homeostasis resulting amelioration marked in, resolution of, people. Meta-analysis demonstrates improvement observed 92% patients accompanied improved 81%, lower 66%, complete 70% NASH.22Mummadi R.R. Kasturi K.S. Chennareddygari Sood G.K. Effect systematic meta-analysis.Clin Gastroenterol 6: 1396-1402Abstract (283) Similarly, weight loss produced intense nutritional counseling reported leading resolution.23Huang M.A. Greenson J.K. Chao Anderson Peterman Jacobson Emick Lok A.S. Conjeevaram H.S. One-year results pilot study.Am Gastroenterol. 2005; 100: 1072-1081Crossref (328) suggest least some pharmacological agents principally target lead when administered making attractive angle (vide infra see Table 1).Table 1Mechanisms Action Associated Pharmacotherapies With Clinical Data NAFLD/NASHMechanism actionDrug nameCurrent statusKey summaryClinicalTrials.Gov identifier studiesLipid pathway modulatorsACC inhibitorPF-05175157 (SM)Ph2—discontinuedSystemically distributed, DNL inhibition, stimulation acid oxidation healthy volunteers. Discontinued due undisclosed safety concernNCT01792635MK-4074 (SM)Ph1—discontinuedLiver directed exposure, lowering subjects; discontinued elevationsNCT01431521GS-0976 (SM)Ph2Liver patientsNCT02856555PF-05221304 subjects doses inhibit ≤80%NCT03448172NCT03248882FAS inhibitorTVB-2640 (SM)Ph2DNL subjectsNone listedDGAT2 inhibitorIONIS-DGAT2rx (ASO)Ph2Ph1 dose-escalation completed overweight subjectsNCT03334214PF-06427878 (SM)Ph1 -discontinuedSteatosis subjects—discontinued PK profileNCT02855177PF-06865571 (SM)Ph1b/Ph2None disclosedNCT03513588NCT03776175Nuclear hormone agonistsPPARγ agonistPioglitazone (SM)Approved T2D, exploratory NASHImprovements NAS, resolution, fibrosisNCT00063622NCT00994682PPARα agonistFenofibrate dyslipidemia, NAFLD/NASHNo apparent direct endpoints small studiesNCT00262964NCT02354976PPARδ agonistGW501516 (SM)Ph2—discontinuedSteatosis NAFLDNAPPARα/δ agonistElafibranor (SM)Ph3Failed meet protocol specified primary endpoint Ph2, modest relative placebo post hoc definition cardio parameters notedNCT01694849NCT02704403PPARα/γ agonistSaroglitazar T2D India, Ph2 NASHNAFLD/NASH pendingNCT03061721FXRObeticholic (SM)Conditional approval PBC, Ph3 all components mild elevations LDL, reductions HDL, pruritusNCT01265498NCT02548351NCT03439254GS-9674 (SM)Ph2Reduction pruritus 100-mg dose; 30-mg dose (currently evaluated ongoing monotherapy combination study) very reduction (3.7%, adjusted)NCT02854605NCT03449446Tropifexor (LJN-452) (SM)Ph2Interim were presented noting ALT content 60- 90-μg doses, decrease HDL. Increased noted doseNCT02855164EDP-305 (SM)Ph2FGF19 increases C4 decreases Ph1. Pruritus decreased HDL (but LDL increase) 20-mg placeboNCT02918929NCT03421431MET409 (SM)Ph1Ph1 ongoingNot postedTHR-β agonistMGL-3196 following 12 36 wk administration. w ≥1-point after administration.NCT02912260VK2809 (SM)Ph2>50% (placebo adjusted) 10-mg daily dose. Increases Ph1 early time points though was different would given robust reductions.NCT02927184FGF peptide mimeticsFGF19NGM 282 (P)Ph257% 45% 6 3-mg ALT, AST, C4. injection site reactions GI AEs who received MGM vs placebo. Improvements NAS non–placebo-controlled 12-wk study.NCT01943045NCT02443116FGF21BMS-986036 (P)Ph2Reductions Pro-C3, MRE 16 studies. (TG, HDL) noted.NCT02413372β-Klotho/FGFR1c agonistNGM313 (MK-3655)Ph1b proof concept normal overweight/obese shows contentNCT02708576NCT03298464Incretin therapiesGLP-1 mimeticsLiraglutide (P)Approved liraglutide 48 wk.NCT01237119Semaglutide NASHRobust control once-weekly once-daily semaglutide. underwayNCT02970942DPP4 inhibitorSitagliptin NASHSitagliptin showed content, double-blinded, placebo-controlled study, earlier, small, open-label, retrospective enzymes NASNCT01963845SGLT2 inhibitorsSGLT1/2 inhibitorLIK066Ph2Ph2 obese ongoingNCT03205150SGLT2 inhibitordapagliflozinPh3Ph3 planned efficacy dapagliflozin NASHNCT03723252Other mechanisms actionMPC inhibitorMSDC-0602K (SM)Ph2A press release Cirius statically AST interim Ph2b trialNCT02784444PXL065 (DRX-065) postedACC, acetyl-CoA carboxylase; alanine aminotransferase; ASO, antisense oligonucleotide; aspartate DGAT, diacylglycerol O-acyltransferase; DNL, novo lipogenesis; DPP4, •••; FAS, synthase; FGF, factor; FXR, Farnesoid X receptor; GLP-1, glucagon-like peptide-1; high-density lipoprotein; MPC, pyruvate carrier; MRE, NAFLD, disease; Disease Activity Score; NASH, steatohepatitis; P, modified peptide; biliary cholangitis; PPAR, SGLT2, sodium glucose co-transporter 2; SM, molecule; diabetes; TG, triglyceride; THR, thyroid receptor. Open table tab ACC, Over nutrition, hyperinsulinemia drives lipogenesis (DNL). Lipogenic transcription factors carbohydrate response element binding (ChREBP) sterol regulatory protein-1c (SREBP-1c) upregulated models, expression lipogenic genes subsequent flux carboxylase (ACC) malonyl-CoA.24Hooper Adams Burnett J.R. determinants man.J Lipid Res. 593-617Crossref (81) suppressed promote 1).24Hooper SREBP1c be NAFLD25Kohjima Enjoji Higuchi Kotoh Yoshimoto Fujino Yada Harada Takayanagi Nakamuta Re-evaluation metabolism-related gene disease.Int Med. 2007; 20: 351-358PubMed 26Pettinelli Del Pozo Araya Rodrigo A.V. Smok Csendes Gutierrez Rojas Korn O. Maluenda Diaz Rencoret Braghetto Castillo Poniachik Videla Enhancement SREBP-1c/PPAR-alpha ratio patients: correlations n-3 long-chain polyunsaturated depletion.Biochim Acta. 2009; 1792: 1080-1086Crossref (127) elevated rates found distinctive characteristic NAFLD.27Lambert J.E. Ramos-Roman Browning Parks E.J. distinct individuals disease.Gastroenterology. 146: 726-735Abstract (290) Humans >3-fold fat, differences between groups detected (FFA) low-density lipoprotein (VLDL) FFAs.27Lambert observation consumption, strongly promotes DNL,28Hudgins L.C. Parker T.S. Levine D.M. Hellerstein M.K. A sugar challenge test sensitivity dietary fructose.J Clin 96: 861-868Crossref (66) NAFLD29Abid Taha Nseir Farah Grosovski Assy Soft drink consumption independent syndrome.J 51: 918-924Abstract (144) 30Ouyang Cirillo Sautin McCall Bruchette J.L. Diehl A.M. Johnson Abdelmalek M.F. Fructose disease.J 48: 993-999Abstract (468) may further underscore importance disease. Fructose-induced likely contributes simple naturally fruit sucrose (table sugar) corn syrup. Dietary trends recent decades demonstrate sharp epidemiological strong correlation fructose-sweetened beverages liver.30Ouyang 31Herman Samuel V.T. sweet path demise: synthesis.Trends 719-730Abstract (56) 32Lim Mietus-Snyder Valente Schwarz Lustig R.H. syndrome.Nat Rev 251-264Crossref (383) 33Stanhope K.L. Havel P.J. Adverse fructose: epidemiological, clinical, mechanistic studies.Curr Opin Lipidol. 24: 198-206Crossref (115) Unlike glucose, whose tightly regulated, rapidly phosphorylated ketohexokinase fructose-1-phosphate without feedback metabolized generate substrates gluconeogenesis lipogenesis. potent inducer than glucose34Hofmann Tschop M.H. sugars: difference.J Invest. 119: 1089-1092Crossref chronic induces ChREBP transcription.31Herman Thus, (ie, inhibition35Huard Ahn Amor Beebe D.A. Borzilleri K.A. Chrunyk B.A. Coffey S.B. Cong Conn E.L. Culp Dowling M.S. Gorgoglione J.A. Knafels Lachapelle E.A. Pandit Parris Perez Pfefferkorn Price Raymer Ross T.T. Shavnya Smith A.C. Subashi T.A. Tesz G.J. Thuma Tu Weaver Weng Withka Magee T.V. Discovery fragment-derived molecules vivo (KHK).J Med Chem. 2017; 60: 7835-7849Crossref (3) limiting diet) represent approaches indicate important inflammatory Berod et al36Berod Friedrich Nandan Freitag Hagemann Harmrolfs Sandouk Hesse Castro C.N. Bahre Tschirner S.K. Gorinski Gohmert Mayer C.T. Huehn Ponimaskin Abraham W.R. Muller Lochner Sparwasser De synthesis controls fate T helper 17 cells.Nat 1327-1333Crossref (258) proinflammatory interleukin-17 secreting cells lineage show dependency produce phospholipids cellular membranes. contrast, anti-inflammatory (Treg) utilize exogenous acids. Inhibition blunts formation Treg. Further, higher frequency Th17 Treg peripheral blood marks humans.37Rau Schilling Meertens Hering Weiss Jurowich Kudlich Hermanns H.M. Bantel Beyersdorf Geier Progression Th17/resting liver.J Immunol. 196: 97-105Crossref Pharmacologic lipotoxicity. Inhibitors synthase (FAS), O-acyltransferase (DGAT) (Table ACC catalyzes first committed step malonyl-CoA adenosine triphosphate–dependent condensation carbonate.38Saggerson Malonyl-CoA, signaling molecule mammalian cells.Annu Nutr. 28: 253-272Crossref (137) Malonyl-CoA allosteric

Language: Английский

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