New insights into activation and function of the AMPK

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(4), P. 255 - 272

Published: Oct. 31, 2022

Language: Английский

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Non-Alcoholic Fatty Liver Disease (NAFLD) Pathogenesis and Natural Products for Prevention and Treatment

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(24), P. 15489 - 15489

Published: Dec. 7, 2022

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic disease, affecting approximately one-quarter of global population, and has become a world public health issue. NAFLD clinicopathological syndrome characterized by hepatic steatosis, excluding ethanol other definite damage factors. Recent studies have shown that development associated with lipid accumulation, oxidative stress, endoplasmic reticulum lipotoxicity. A range natural products been reported as regulators in vivo vitro. This paper reviews pathogenesis some to therapeutic effects on NAFLD. Our work shows can be potential option for

Language: Английский

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The AMPK pathway in fatty liver disease

Frontiers in Physiology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 25, 2022

Lipid metabolism disorders are the primary causes for occurrence and progression of various liver diseases, including non-alcoholic fatty disease (NAFLD) alcoholic (AFLD) caused by a high-fat diet ethanol. AMPK signaling pathway plays an important role in ameliorating lipid disorders. Progressive research has clarified that signal axes involved prevention reduction injury. Upregulation AMK can alleviate FLD mice induced alcohol or insulin resistance, type 2 diabetes, obesity, most natural agonists regulate metabolism, inflammation, oxidative stress hepatocytes, consequently regulating mice. In NAFLD AFLD, increasing activity inhibit synthesis acids cholesterol down-regulating expression adipogenesis gene (FAS, SREBP-1c, ACC HMGCR); Simultaneously, acid oxidation decomposition genes (CPT1, PGC1, HSL, ATGL) decomposition, body’s balance be maintained. At present, some activators thought to beneficial during therapeutic treatment. Therefore, activation is potential target liver. We summarized recent on this review. we performed detailed description each axis pathway, as well discussion its mechanism action significance.

Language: Английский

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Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis

Advanced Drug Delivery Reviews, Journal Year: 2021, Volume and Issue: 176, P. 113888 - 113888

Published: July 24, 2021

Language: Английский

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NAFLD and NASH: etiology, targets and emerging therapies

Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(3), P. 103910 - 103910

Published: Feb. 1, 2024

Language: Английский

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SLC7A11-ROS/αKG-AMPK axis regulates liver inflammation through mitophagy and impairs liver fibrosis and NASH progression

Redox Biology, Journal Year: 2024, Volume and Issue: 72, P. 103159 - 103159

Published: April 16, 2024

The changes of inflammation and metabolism are two features in nonalcoholic steatohepatitis (NASH). However, how they interact to regulate NASH progression remains largely unknown. Our works have demonstrated the importance solute carrier family 7 member 11 (SLC7A11) metabolism. Nevertheless, whether SLC7A11 regulates through mediating is unclear. In this study, we found that expression was increased liver samples from patients with NASH. Upregulated level also detected murine models. Functional studies showed knockdown or knockout had augmented suppression inflammatory markers mice. overexpression dramatically alleviated diet-induced pathogenesis. Mechanically, decreased reactive oxygen species (ROS) promoted α-ketoglutarate (αKG)/prolyl hydroxylase (PHD) activity, which activated AMPK pathway. Furthermore, impaired NLRP3 inflammasome components AMPK-mitophagy axis. IL-1β release recruited myeloid cells hepatic stellate (HSCs) activation, contributed injury fibrosis. Anti-IL-1β anakinra might attenuate response evoked by knockdown. Moreover, upregulation lipid overload-induced JNK-c-Jun conclusions, acts as a protective factor controlling development Upregulation regulating oxidation, αKG energy metabolism, decreasing

Language: Английский

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Mitochondria‐Targeted Nanoadjuvants Induced Multi‐Functional Immune‐Microenvironment Remodeling to Sensitize Tumor Radio‐Immunotherapy

Advanced Science, Journal Year: 2024, Volume and Issue: 11(26)

Published: May 5, 2024

Abstract It is newly revealed that collagen works as a physical barrier to tumor immune infiltration, oxygen perfusion, and depressor in solid tumors. Meanwhile, after radiotherapy (RT), the programmed death ligand‐1 (PD‐L1) overexpression transforming growth factor‐β (TGF‐β) excessive secretion would accelerate DNA damage repair trigger T cell exclusion limit RT efficacy. However, existing drugs or nanoparticles can hardly address these obstacles of highly effective simultaneously, effectively, easily. In this study, it inducing mitochondria dysfunction by using oxidative phosphorylation inhibitors like Lonidamine (LND) serve multi‐immune pathway regulation strategy through PD‐L1, collagen, TGF‐β co‐depression. Then, IR‐LND prepared combining mitochondria‐targeted molecule IR‐68 with LND, which then loaded liposomes (Lip) create IR‐LND@Lip nanoadjuvants. By doing this, more effectively sensitizes generating cold tumors into hot ones activation co‐inhibition. conclusion, combined treatment ultimately almost completely suppressed bladder breast

Language: Английский

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Triterpenoids from Chios Mastiha Resin Against MASLD—A Molecular Docking Survey

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(1), P. 51 - 51

Published: Jan. 15, 2025

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic without an approved pharmacological approach for its prevention/treatment. Based on modified Delphi process, NAFLD was redefined as metabolic dysfunction-associated steatotic (MASLD) to highlight aspect of pathogenesis. Chios mastiha (Pistacia lentiscus var. Chia, Anacardiaceae) resin demonstrated promising results in MASLD treatment. In this paper, molecular docking applied test 16 compounds from potential ligands receptors GR, LXRα, LXRβ, PPARα PPARγ, MC4R, AMPK, and VEGFR2, whose up- down-regulation interfere with development progression. The observed had moderate high affinity LXR, PPARγ comparison proven ligands, while their PPARα, VEGFR less pronounced. combination active rather than a single molecule may have superior ability control intertwined pathways.

Language: Английский

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Hepatoprotective effects of polysaccharide from Morchella esculenta are associated with activation of the AMPK/Sirt1 signaling pathway in mice with NAFLD

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 301, P. 140444 - 140444

Published: Jan. 28, 2025

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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