Karaciğer yağlanması
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Karaciğer yağlanması
- 1. Karaciğer Yağlanması Hamed HAJİZADEH Danışman: Prof. Dr. Birgül KURAL 28.11.2016
- 2. Sunu Planı: 2 Karaciğer Karaciğer Yağlanması Karaciğer Yağlanması Çeşitleri Alkol Metabolizması Alkole Bağlı Karaciğer Yağlanması Alkolik Olmayan Karaciğer Yağlanması Gebelikte Akut Karaciğer Yağlanması Özet
- 3. Karaciğer 3 Yapı * 1.5-2 kg * %60 hepatosit, %30 endotel hücreler ve %10 kupfer hücreleri ve bağ dokusundan oluşmaktadır. Yağ AsitleriKeton Cisimleri HDL VLDL HDL Fosfolipidler Kan Plazma Proteinleri: Albumin, α1, , α 2, β-globülinler, pıhtılaşma faktörleri Koenzimler: NAD, NADP, FMN Amino asitler Ürik asit Üre Bilirubinİndol Skatol Fenol Benzoik asit Detoksifikasyon Glisin Glukoronid Monosakkaritler Amino asitler Safra Kolesterol Safra asitleri Bilirubin Laktat Kan glukozu İnce bağırsak Kalın bağırsak Lipidler Fonksiyon * Metabolizma * Detoksifikasyon * Sentez ve Salgılama * Depo
- 4. Karaciğer Yağlanması: 1980: Ludwig →→→ ″Nonalcoholic steatohepatitis (NASH)′′ Karaciğer Yağlanması (hepatosteatoz): Karaciğer ağırlığının %5’den fazlasının yağ olması. 4 Steato- (Yağlı) Hepatic (Karaciğer) Steatohepatitis
- 5. Karaciğer Yağlanması (Hepatosteatoz-HS) Çeşitleri: 1) Alkolik Karaciğer Yağlanması (Alkolik Hepatosteatoz- AHS) 2) Non Alkolik Karaciğer Yağlanması (NAKY) 3) Gebeliğe Bağlı Akut Karaciğer Yağlanması 5Doç. Dr. Dilek TOPRAK. Hepatosteatoz (Yağlı Karaciğer Hastalığı). turkishfamilyphyscian; 2:2; 50-57.
- 6. Alkol Metabolizması 6Samir Zakhari (2013). Alcohol etabolism and Epigenetics Changes. Alcohol Research: 6-17. ADH: alcohol dehydrogenase, ALDH2: aldehyde dehydrogenase 2, CYP2E1: Cytochrome P450 2E1, ROS: Reactive oxygen species
- 7. 7 NADH/NAD+ oranının artmasıyla; Glukoneojenez baskılanır ve hipoglisemi gelişebilir. watcut.uwaterloo.ca/webnotes/Metabolism/Gluconeogenesis.html
- 8. 8 Artmış NADH/NAD+ Oranının Metabolik Sonuçları Samir Zakhari and Ting-Kai Li (2007). Determinants of Alcohol Use and Abuse: Impact of Quantity and Frequency Patterns on Liver Disease. HEPATOLOGY, Vol. 46, No. 6; 2032-2039.
- 9. Molina PE. Alcohol--intoxicating roadblocks and bottlenecks in hepatic protein and lipid metabolism. Am J Physiol Endocrinol Metab. 2008 Jul;295(1):E1-2. 9
- 10. 10 Alkolik Karaciğer Gelişimindeki Lipin-1’in Rolü Lijuan Bi, Zhian Jiang and Junying Zhou (2015). The Role of Lipin-1 in the Pathogenesis of Alcoholic Fatty Liver. Alcohol and Alcoholism Vol. 50, No. 2, 146–151. AMPK, adenosine monophosphate activated kinase; miR-217, microRNA-217; SIRT1, sirtuin1; SREBP-1, sterol regulatory element binding protein 1; PAP, phosphatidic acid phosphohydrolase; SFRS10, splicing factor, arginine/serine-rich 10; VLDLTAG, very low- density lipoprotein-triacylglyceride; PPARα, peroxisome proliferator-activated receptor α; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α.
- 11. Zakhari S. Alcohol metabolism and epigenetics changes. Alcohol Res. 2013;35(1):6-16. 11 Alkol Metabolizması ile Epigenetik Mekanizmalar Arasındaki Etkileşimler SAM: S-adenosylmethionine, DNMTs: DNA methyltransferases, HMTs: histone methyl transferases, AMPK: AMP-activated protein kinase, HAT: histone acetyl transferase, TCA: tricarboxylic acid cycle.
- 12. 12 Alkol Metabolizması ve Histon Asetilasyonu Samir Zakhari (2013). Alcohol etabolism and Epigenetics Changes. Alcohol Research: 6-17. AceCS1: acetyl-CoA synthetase, HAT: histone acetyltransferase, SIRT1: Sirtuin1
- 13. 13Varela-Rey M et al. Alcohol, DNA methylation, and cancer. Alcohol Res. 2013;35(1):25-35. Etanolün Folat, SAM ve Metiyonin Üzerine İnhibitör Etkileri BHMT: betaine homocysteine methyltransferase; DHF: dihydrofolate; DHFR: dihydrofolate reductase; DNMT: DNA methyltransferase; dTMP: deoxythymidine monophosphate; dUMP: deoxyuridine monophosphate; Hcy: homocysteine; MAT: methionine adenosyl transferase; Met: methionine; MT: methyltransferase; 5-MTHF: 5-methyltetrahydrofolate; 5,10-MTHF: 5,10- methylenetetrahydrofolate; MTHFR: methylenetetrahydrofolate reductase; MTR: methionine synthase; SAH: S-adenosylhomocysteine; SAMe: S- adenosylmethionine; THF: tetrahydrofolate; TS: thymidylate synthase.
- 14. Hepatik Uydu Hücreleri Üzerine Etanolün Profibrotik Etkileri Wang JH, Batey RG, George J. Role of ethanol in the regulation of hepatic stellate cell function. World J Gastroenterol. 2006; 12(43):6926-32. 14
- 15. Moghe A et al. Histone modifications and alcohol-induced liver disease: are altered nutrients the missing link? World J Gastroenterol. 2011 May 28;17(20):2465-72. 15 Besin Bozuklukları, Alkol ile Metabolize Olma ve Histon Değişiklikleri Arasındaki İlişki SAM: S-adenosylmethionine; HAT: Histone acetyltransferase; HDAC: Histone deacetylase
- 16. Alkolik Karaciğer Yağlanması (Alkolik Hepatosteatoz- AHS) * Günlük 60 g üstünde alkol alımı yağlı karaciğere yol açar. * Cins: Kadın – Erkek ?! * Beslenme bozukluğu * Hepatik demir miktarı artmaktadır. 16
- 17. 17 Alkolik Karaciğer Yağlanmasi Alkolik Hepatit Alkolik Siroz
- 18. 18 Alkolik Karaciğer Hastalıklarında Fizik Muayene Bulguları Gökhan KÖKER, Yasin ŞAHİNTÜRK, Ayhan Hilmi ÇEKİN (2015). Alkolik Karaciğer Hastalıkları. güncel gastroenteroloji 19/2; 104-111.
- 19. Neuman MG. Cytokines--central factors in alcoholic liver disease. Alcohol Res Health. 2003;27(4):307-16. 19
- 20. Non Alkolik Yağlı Karaciğer Hastalığı (NAYKH/NAFLD) 1) Nonalkolik Hepatosteatoz (NAHS-Nonalkolik karaciğer yağlanması): Karaciğerde yağlanma İltihabi infiltrasyon 2) Nonalkolik Steatohepatit (NASH): Karaciğerde yağlanma Hepatositlerde balonlaşma İltihabi infiltrasyon Mallory cisimcikleri Megamitokondria Fibrozis 20
- 21. Non Alkolik Yağlı Karaciğer Patogenezi * Obezite * İnsülin Direnci * Metabolik Sendrom * İki Vuruş Hipotezi * Çoklu Vuruş Hipotezi 21 Prof. Dr. Abdullah Sonsuz (2007). Nonalkolik Karaciğer Yağlanması. TÜRKİYEDE SIK KARŞILAŞILAN HASTALIKLAR II. Sempozyum Dizisi No:58; 91-98.
- 22. 22 Liang Xu, Hironori Kitade, Yinhua Ni and Tsuguhito Ota (2015). Roles of Chemokines and Chemokine Receptors in Obesity-Associated Insulin Resistance and Nonalcoholic Fatty Liver Disease. Biomolecules 5(3), 1563-1579. NAYKH’nın Başlatıcı Faktörler ve Mekanizmaları
- 23. NAYKH ve İnsülin Direnci 23 Hormona duyarlı lipoprotein lipaz Mitokondriyal β oksidasyon Trigliseridlerin esterleşmesi VLDL CYP2E1 ekspresyonu Leon A. Adams, Paul Angulo, Keith D. Lindor (2005). Nonalcoholic fatty liver disease. CMAJ 172 no. 7 899-905
- 24. Yki-Järvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2014; 2(11):901-10. 24 NAYKH ve Metabolik Sendrom ile İlişkisi alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyltransferase (GGT), C-reactive protein (CRP), fibroblast growth factor 21 (FGF21), coagulation factors, FVII–IX, FXI–XII.
- 25. Leong PK, Ko KM. Schisandrin B: A Double-Edged Sword in Nonalcoholic Fatty Liver Disease. Oxid Med Cell Longev. 2016;2016:6171658. Epub 2016 Oct 26. 25 NAYK’in Patogenezi SREBP1: sterol regulatory element-binding protein-1; ACC: acetyl-CoA carboxylase; FAS: fatty acid synthase; ATGL: adipose triglyceride lipase; HSL: hormone-sensitive lipase; GI tract: gastrointestinal tract; TNF-𝛼: tumor necrosis factor- 𝛼; IL-6: interleukin-6; ROS: reactive oxygen species; ER: endoplasmic reticulum; PDGF: platelet-derived growth factor; TGF-𝛽: transforming growth factor-𝛽; ECM: extracellular matrix.
- 26. Olav A Gressner et al (2007). Evolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options. Comparative Hepatology, 6:7; 1-13. Fibroza Gidiş 26
- 27. He Z, Hu C, Jia W. miRNAs in non-alcoholic fatty liver disease. Front Med. 2016 Sep 28. 27 NAYKH Patogenezinde Yer Alan miRNA'lar
- 28. Non Alkolik Yağlı Karaciğer Heterogeniti Patatin-like phospholipase domain-containing protein 3 (PNPLA3) (Adiponutrin) I148M’yi kodlayan rs738409 alleli KC’de yağ oranını artırmakla hepatik inflamasyon, fibroz, siroz ve hepatosellüler karsinoma riskini arttırır. (dünya çapındaki sıklığı %30-%50). Transmembrane 6 superfamily member 2 gene (TM6SF2) Bir başka ve daha az yaygın olan polimorfizm (%15 sıklıkla), E167K varyantı NAYK hastalığına duyarlılık kazandırır. ’’TM6SF2 NAYK’’ olan kişilerde NASH riski , insüline direnç , dolaşımdaki trigliseritleri normaldır. TM6SF2’nin hepatik knockdown’ı VLDL salınımını düşürmektedir. Hannele Yki-Järvinen (2015). Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance. Nutrients 7, 9127–9138. 28
- 29. S.A. Townsend and Philip N. Newsome (2016). Non- alcoholic fatty liver disease in 2016. British Medical Bulletin, 119:143–156. 29 NAYKH’da bu LPS’lerin temizlenmesinin bozulmasına inanılır ve kademeli olarak bakterilerin aşırı çoğalmasına neden olup, bağırsak geçirgenliği, enflamatuar sitokinlerin ve kemokinlerin uyarılması arttırılır ki bu da hepatik hasar ve fibroz ile sonuçlanır. Son zamanlarda, bağırsak florası NAYKH’da steatohepatit ve fibrozun gelişiminde potansiyel bir role sahip olduğu gösterilmiştir. Gram-negatif bağırsak mikroflorasından gelen lipopolisakkaridler bağırsak kılcal damarlar tarafından emilir ve portal sisteme girer, hepatositler üzerinde toll-like reseptörler (TLR), Kupffer hücreler ve hepatik uydu hücrelerini aktive eder ve pro-enflamatuar etkisini uygular. NAYK Hastalığına Neden Olan Diğer Etkenler
- 30. 30 NAYKH'nın Histolojik Özellikleri Elizabeth M. Brunt et al (2015). Nonalcoholic fatty liver disease. NATURE REVIEWS. 15080-(1) 1-22. a) Steatoz b) Steatoz, lobuler ve portal inflamasyon ve balonlaşma c) Fibroz ve köprüleşme d) NASH ile birlikte siroz e) Hepatosellüler karsinoma
- 31. 31 Gebeliğin Akut Yağli Karaciğeri İlk olarak Stander ve Cadden tarafından 1934 yılında akut sarı atrofik karaciğer olarak tanımlanan gebeliğin akut yağlı karaciğeri (GAYK) obstetrik acillerdendir. - Gebeliğin 2. yarısında görülen hepatositlerin mikroveziküler yağlanması olarak tarif edilir. - GAYK mitokondriyal β oksidasyon bozukluğundan kaynaklanmaktadır. - İç mitokondri membranı üzerinde yer alan mitokondri enzim kompleksinin bir parçası olan uzun zincirli 3-hidroksi açil koenzim A dehidrogenaz (LCHAD) enzim eksikliği bir ya da her iki allelde G1528C ve E474Q mutasyonları sonucu ortaya çıkar.
- 32. 32Woo-Suk Han et al (2012). Acute fatty liver of pregnancy with fetal microvesicular hepatic steatosis. Korean J Obstet Gynecol. 55(9):649-654.
- 33. 33Sonay GÜVEN, Cansel TÜRKAY (2011). Gebelik ve Karaciğer Hastalıkları. güncel gastroenteroloji 1 5 / 2; 107-113. DIC: Disseminated Intravascular Coagulation
- 34. 34 Karaciğer Yağlanması Tanısında Yararlı Olan Biyobelirteçler Karaciğer fonksiyon testleri ALT, AST, ALP, GGT, ferritin Adipokinler Adiponektin, leptin, resistin, visfatin, PPAR Sitokinler TNF-α, IL-6, IL-8, fibroblast büyüme faktörü 21, Tol-like reseptör 4 kompleks, CRP, NF-кB Oksidatif stres Lipid, DNA ve protein oksidasyon belirteçleri, Nitrozatif stres biyobelirteçleri ve antioksidanlar Fibrozis AST/ALT oranı, APRI, PGA indeks, Fibroindeks, Fibrometer, FibroTest, FIB-4 indeks, hepaskor, prokollajen tip I C-terminal peptid, prokollajen tip III N-terminal peptid Matriks birikimi Tip I ve IV kollajenler, laminin, hiyaluronik asit, YKL-40 Matriks yıkımı MMP-2, MMP-9 Diğer TGF-β, Hepatosit apoptoz belirteci sitokeratin-18 Prof. Dr. Dildar Konukoğlu (2016). Sorularla Konu Anlatımlı Tıbbi Biyokimya. Nobel Tip Kitabevi
- 35. NASH Biyobelirteçleri Sitokeratin-18 (CK-18) %78 hassasiyet ve %87 duyarlılıkla bazı örnek çalışmalarda NASH taranması için potansiyelini sergilemektedir. 35Hyunwoo Oh et al (2016). Non-alcoholic fatty liver diseases: update on the challenge of diagnosis and treatment. Clin Mol Hepatol. 22(3): 327–335.
- 36. Özet Karaciğer Yağlanması Gebeliğe Bağlı Akut Karaciğer Yağlanması Alkolik Karaciğer Yağlanması Non Alkolik Karaciğer Yağlanması Günlük 60 g alkol NADH/NAD+ Lipogenez Oksidatif Stres ROS AMPK ↓ Protein ve DNA sentezi ↓ Glutatyon ↓ Lakto asidoz Obezite, İnsülin direnci ve Metabolik sendrom TG ve VLDL metabolizması Mitokondriyal β oksidasyon ↓ Adipoz doku Kemokin Adiponektin ↓ Aktifleşmiş kupfer hücreleri Adiponutrin ve TM6SF2 LCHAD enzim eksikliği 3. Trimester Fetüs KC.’nde yağ birikimi Maternal metabolik stres Çevresel stres Yağlı beslenme
- 39. 39Elmar Aigner et al (2008). Pathways underlying iron accumulation in human nonalcoholic fatty liver disease. Am J Clin Nutr 2008;87:1374–83.
- 40. 40
- 41. 41
- 42. 42Elmar Aigner, Günter Weiss, Christian Datz (2015). Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver. World J Hepatol; 7(2): 177-188.
- 43. 43Christian Riehle, E. Dale Abel. Insulin Signaling and Heart Failure. Circ Res. 2016;118:1151-1169.
- 44. 44
Notes de l'éditeur
- Sebebi ne olursa olsun karaciğerde yağlanmanın saptandığı bütün klinik tablolar. (LCHAD esikliği) Gebeliğe bağlı akut karaciğer yağlanması gelişen kadınlarda, bazı yağ asitlerini işleyen bir enzimde genetik olarak hafif yetmezlik vardır. Hamile değilken sorun yoktur. Ancak bu kadınlar hamile kalırlar ve bebeğe de genetik olarak bu enzim eksikliği geçerse, bebekte işlenemeyen yağ asitleri de anneye geçer. Anne bunun üstesinden gelemez ve annenin karaciğer hücrelerinde yağ birikir.
- Like gluconeogenesis, ethanol degradation occurs in the liver. The utilization of one molecule of ethanol by alcohol dehydrogenase and then aldehyde dehydrogenase yields acetate, which is converted to acetyl-CoA by acetate thiokinase. For each molecule of ethanol degraded, two equivalents of NAD+ are reduced to NADH. This raises the cytosolic [NADH]/[NAD+] ratio, which in turn reduces both pyruvate and oxaloacetate and thus deprives gluconeogenesis of its substrates. In alcoholic patients, this problem is often compounded by a low intake of carbohydrates. Clinically manifest hypoglycemia with unconsciousness is a well-known and potentially dangerous complication in alcohol addiction. Instead, NADH accumulation in the cytosol favors the conversion of pyruvate to lactate by LDH. This lowers the concentration of pyruvate, which in turn decreases the pyruvate carboxylase reaction, one of the rate limiting steps of gluconeogenesis (Krebs et al. 1969). Collectively, the increase in NADH results in the inhibition of gluconeo genesis and, during starvation, can cause clinically significant hypoglycemia.
- Fig. 3. Alcohol metabolism to acetaldehyde in the cytosol by ADH and then to acetate by mitochondrial ALDH2 increases the ratio of NADH to NAD. NADH in the mitochondria is oxidized via the ET chain. Pyruvate in the cytosol is formed from glucose via glycolysis and can undergo three pathways: (1) entering the mitochondria to form acetyl CoA by oxidative decarboxylation with PDH; (2) being reduced to lactate by LDH, a process that requires NADH; or (3) being converted to glucose (gluconeogenesis) via an ATP-requiring reaction. Almost all of the acetate formed from acetaldehyde metabolism cannot be converted to acetyl CoA and enters the circulation to be metabolized by extrahepatic tissues. The increase in cytosolic NADH favors the formation of lactate resulting in lactic acidosis, and in the mitochondria forms HB from acetoacetate by BHB dehydrogenase. ADH indicates alcohol dehydrogenase; ADP, adenosine diphosphate; ALDH2, aldehyde dehydrogenase 2; ATP, adenosine triphosphate; HB, -hydroxybutyrate; CoA, coenzyme A; ET, electron transport; NAD, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; TCA, tricarboxylic acid; and VLDL, very low density lipoprotein.
- Alcohol oxidation to acetaldehyde may occur through cytosolic alcohol dehydrogenase (ADH), cytochrome P-450 2E1, or peroxisomal catalase (in that order of importance). Acetaldehyde is oxidized to acetate by mitochondrial aldehyde dehydrogenease (ALDH2). Products of this metabolic pathway result in cellular depletion of S-adenosylmethionine (SAMe) and increased levels of homocysteine, acetaldehyde, and reactive oxygen species (ROS). Together, these factors cause an unfolded-protein response in the endoplasmic reticulum (ER) called ER stress. This activates sterol regulatory element-binding proteins (SREBP-1c and -2c), resulting in triglyceride accumulation. AMP kinase (AMPK), a key regulator of metabolism, drives fatty acid (FA) oxidation and export through activation of peroxisome proliferator-activated receptor-α (PPARα); suppresses SREBP-1c, decreasing lipogenesis; and inhibits acetyl-CoA carboxylase (ACC), which through decreased malonyl-CoA levels and carnitine palmitoyltransferase I (CPT I) activity decreases synthesis and increases oxidation of fatty acids. Activity of AMPK is inhibited by alcohol, ER stress, tumor necrosis factor (TNF), and ROS. Adiponectin released from adipose tissue, which activates AMPK, is in turn suppressed by chronic alcohol consumption. All together, these alcohol-induced effects lead to deranged lipid metabolism and development of fatty liver. Hepatic protein synthesis is suppressed through what appears to be a roadblock in peptide chain initiation. The key step affected by alcohol involves the inability of cycling between the active and inactive forms of the eIF2·eIF2B complex, preventing the formation of the 43S preinitiation complex. Moreover, with chronic alcohol exposure, the defect extends to the ability of the eIF4 complex to effectively regulate the association between the 43S complex and the 5′ cap of mRNA to form the 48S preinitiation complex (pre-IC). Defects in the protein synthetic pathway appear to be the result of a possible dysregulation between the kinase and phosphatase involved in phosphorylation of selected initiation factors. The upstream signals involved are yet to be fully elucidated. Red dotted lines, inhibition of pathway or activation; green solid lines, stimulation or activation of pathway.
- microRNA-217 (miR-217) is frequently dysregulated in cancer. Ethanol increases the expression of lipin-1 through the AMPK-SREBP-1 signaling and the ratio of lipin-1β to lipin-1α through SIRT1-SFRS10- Lpin1β/α axis in liver. In cytoplasm, lipin-1β as PAP enzyme converts PA to DAG. In nucleus, lipin-1α directly interacts with PCG-1α and PPARα to induce fatty acid oxidation. Lipin-1α could also inhibit the activity of SREBP-1, decreasing the synthesis of fatty acid. Over-expression of lipin-1 could suppress VLDL-TAG secretion. Endogenous lipin-1 has potent anti-inflammatory property. AMPK, adenosine monophosphate activated kinase; miR-217, microRNA-217; SIRT1, sirtuin1; SREBP-1, sterol regulatory element binding protein 1; PAP, phosphatidic acid phosphohydrolase; SFRS10, splicing factor, arginine/serine-rich 10; VLDLTAG, very low-density lipoprotein-triacylglyceride; PPARα, peroxisome proliferator-activated receptor α; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α.
- Chronic alcohol consumption leads to lower-than-normal methylation (i.e., hypomethylation) by decreasing the levels of S-adenosylmethionine (SAM), which is used by DNA methyltransferases (DNMTs) and histone methyl transferases (HMTs) to methylate DNA and histones, respectively. Furthermore, alcohol metabolism increases the ratio of the reduced nicotinamide adenine dinucleotide (NADH) to the oxidized nicotinamide adenine dinucleotide (NAD+); this inhibits SIRT1, thereby interfering with normal histone acetylation patterns. ATP = Adenosine triphosphate; AMPK = AMP-activated protein kinase; HAT = histone acetyl transferase; TCA = tricarboxylic acid cycle.
- Alcohol metabolism and histone acetylation. Acetyl-coenzyme A (acetyl-CoA) synthetase (AceCS), an enzyme that converts acetate to acetyl-CoA, is activated by SIRT1. Acetyl-CoA is used by histone acetyltransferase (HAT) to acetylate the lysine residues in histone proteins. This neutralizes the positive charge and allows the chromatin to assume an open conformation, thus resulting in gene activation. SIRT1 also deaceytlates acetylated histones, resulting in gene silencing. Thus, SIRT1 is a sensor that balances gene activation and silencing in the cell based on the cell’s energy status. Alcohol metabolism results in acetate formation, which is used in extrahepatic tissues to produce acetyl-CoA.
- One-carbon metabolism with a schematic representation of the role of methionine in folate metabolism and transmethylation reactions and steps that are inhibited by alcohol. BHMT: betaine homocysteine methyltransferase; DHF: dihydrofolate; DHFR: dihydrofolate reductase; DNMT: DNA methyltransferase; dTMP: deoxythymidine monophosphate; dUMP: deoxyuridine monophosphate; Hcy: homocysteine; MAT: methionine adenosyl transferase; Met: methionine; MT: methyltransferase; 5-MTHF: 5-methyltetrahydrofolate; 5,10-MTHF: 5,10-methylenetetrahydrofolate; MTHFR: methylenetetrahydrofolate reductase; MTR: methionine synthase; SAH: S-adenosylhomocysteine; SAMe: S-adenosylmethionine; THF: tetrahydrofolate; TS: thymidylate synthase. several mechanisms may mediate the effects of alcohol on dna methylation, including reduced folate levels and inhibition of key enzymes in one-carbon metabolism that ultimately lead to lower saMe levels, as well as inhibition of activity and expression of enzymes involved in dna methylation (i.e., dna methyltransferases). Finally, variations (i.e., polymorphisms) of several genes involved in one-carbon metabolism also modulate the risk of alcohol-associated carcinogenesis.
- Possible mechanisms for the direct profibrotic effects of ethanol on hepatic stellate cells. Acetaldehyde, together with ethanol or acetaldehyde-derived oxidative stress, induces latent TGFβ1 and TGFβ receptor activation that subsequently leads to Smad3/4 activation and binding to the promoter of collagen I genes. PKC and/or PI-3K kinases are also activated by acetaldehyde. Both kinase systems activate their downstream components, including ERK1/2 and JNK. As a result, C/EBP, NF-1 and/or BTEB transcription factors are activated and therefore up-regulate collagen I gene transcription. Ethanol and acetaldehyde directly promote the production of transforming growth factor beta-1 (TGFβ-1) and several extracellular matrix (ECM) constituents including type I collagen by HSCs[8,9,11]. Chronic ethanol consumption does not influence ADH activity, but has a profound stimulatory effect on microsomal enzymes, particularly CYP2E1[1,2]. This is in part responsible for the development in alcoholic liver diseases, a rise in oxygen consumption, the excessive production of free radicals and an increase in the metabolism of ethanol, vitamin A and testosterone. Ethanol and acetaldehyde have deleterious effects both direct and indirect, for example by generating reactive oxygen species (ROS) and causing damage to the intestinal mucosal barrier[1,10]. Cellular oxidative stress that is caused by the relative imbalance between free radical generation and insufficient anti-oxidant defense mechanisms, including reductions in glutathione, vitamin E and phosphatidylcholine, may be a principal mediator for the progression of alcoholic liver disease
- Besin bozuklukları, alkol ile metabolize olma ve alkol ile indüklenen karaciğer hastalığında histon değişiklikleri arasında potansiyel bir ilişki. SAM: S-adenosylmethionine; Nutrients can dramatically affect gene expression and alcohol-induced nutrient imbalance may be a major contributor to pathogenic gene expression in alcohol-induced liver disease (ALD). There is growing interest regarding epigenetic changes, including histone modifications that regulate gene expression during disease pathogenesis. Notably, modifications of core histones in the nucleosome regulate chromatin structure and DNA methylation, and control gene transcription. NAD+: Nicotinamide adenine dinucleotide; HAT: Histone acetyltransferase; HDAC: Histone deacetylase; ALD: Alcohol-induced liver disease.
- Alkolü metabolize eden karaciğer dışı dokulardan en önemlisi mide mukozasında bulunan alkol dehidrogenazdır. mide mukozasında bulunan alkol dehidrogenaz etkinliği erkeklerde kadınlara göre yaklaşık 2 kat daha yüksektir.
- Pathways through which alcohol (ethanol) can contribute to apoptosis. Alcohol is broken down (i.e., metabolized) in the liver cells by two enzymes, alcohol dehydrogenase (ALD) and, particularly after chronic alcohol consumption, cytochrome P450 2E1 (CYP2E1). Both enzymes convert alcohol to acetaldehyde, a toxic substance. Some of the acetaldehyde interacts with proteins in the cells, forming compounds called adducts that can activate certain immune cells to produce various cytokines, including interleukins (ILs), interferon gamma (IFN–γ), and tumor necrosis factor alpha (TNF–α). In addition to acetaldehyde, alcohol metabolism by CYP2E1 also generates highly reactive molecules known as reactive oxygen species (ROS), which accumulate primarily in cell structures called mitochondria. ROS normally are eliminated from the cells by compounds known as antioxidants, particularly a small molecule called glutathione (GSH). Alcohol, however, depletes the cell’s GSH stores, thereby further exacerbating ROS accumulation in the mitochondria. This process leads to the release of cytochrome c from the mitochondria, which then activates enzymes called caspases and promotes production of IL–8 in the cell. Finally, alcohol leads to increased levels of a bacterial protein called endotoxin in the blood and in the liver, which activates immune cells called Kupffer cells that reside in the liver. These cells then produce TNF–α, which in turn activates another type of liver cell, the stellate cells, to produce transforming growth factor beta (TGF–β) and collagen, a protein involved in scar tissue formation (fibrosis). TNF–α production also leads to increased production of chemokines (e.g., IL–8), which attract inflammatory cells from the bloodstream to the liver, contributing to liver inflammation. Excess TNF–α and chemokine production also causes increased production of adhesion molecules that play an important role in fibrosis. Thus, all of these diverse pathways contribute to inflammatory reactions and fibrosis and culminate in the induction of apoptosis and organ damage.
- Pathomechanisms during the progression to NASH. The development of NASH is initiated by several different risk factors including a high-fat diet, physical inactivity, and genetic predispositions that often lead to obesity and insulin resistance. Exaggerated fat intake and obesity lead to hyperglycemia, hyperlipidemia, and the over expressions of adipocytokines and chemokines and further contribute to insulin resistance in adipose tissue and the liver. Insulin resistance results in hepatic triglyceride (TG) synthesis and the increased delivery of free fatty acids (FFAs) to the liver. Additionally, hepatic steatosis acts as a “first hit” that is followed by a “second hit” in which inflammatory mediators can cause NASH and even cirrhosis. An enhanced storage of TG provokes a series of harmful consequences related to hepatocytes, such as uncontrolled lipid peroxidation, oxidative stress, and endoplasmic reticulum (ER) stress, which can activate hepatic inflammatory pathways. In particular, the recruitment of macrophage/Kupffer cells and an M1-dominant phenotypic shift in macrophages in the liver play a key role in the pathological progression of NASH.
- Karaciğer insülin direnci ve metabolik sendromun iki anahtar bileşeni olan hiperglisemi ve yüsek seviyede VLDL’nin oluşum merkezidir. Kilolu ve inaktiviteye atfolunabilir NAYK hastalığı bulunan kişilerde insülinin normal koşullardaki glukoz ve VLDL oluşumunu baskılama yeteneği bozulur. Hiperglisemi insülin salgılanmasını uyarır ve böylece hiperinsülinemi indükler. VLDL’nin yüksek konsantrasyonu, HDL kolesterol seviyesinin düşürülmesine ve yüksek oranda aterojenik olduğu bilinen küçük yoğun LDL parçacıklarının üretilmesine yol açar. karaciğer, bir kez yağlı karaciğer, aynı zamanda, C-reaktif protein ve koagülasyon faktörleri gibi kardiyovasküler risk belirteçlerini fazla miktarda üretir. Hannele Yki-Järvinen (2015). Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance. Nutrients 7, 9127–9138.
- Pathophysiology of non-alcoholic fatty liver disease (NAFLD), causes and consequences of which resemble those of metabolic syndrome. Aşırı beslenme, özellikle aşırı basit şekerler ve fiziksel hareketsizlik NAFLD'ye ve metabolik sendroma yatkınlığa neden olur. Excess sugars are converted into intrahepatocellular triglycerides in the liver via de-novo lipogenesis, which is increased in NAFLD. In patients with NAFLD, even compared with equally obese individuals, adipose tissue is hypoxic and contains dead adipocytes surrounded by macrophages and bioactive lipids such as ceramides, which might contribute to insulin resistance in adipose tissue. Expression of multiple cytokines such as tumour-necrosis factor and chemokines such as monocyte chemoattractant protein-1 is increased in adipose tissue. Adipose tissue becomes resistant to the action of insulin to inhibit release of non-esterified fatty acids and secretes decreased amounts of the insulin-sensitising cytokine adiponectin. These two changes promote synthesis of intrahepatocellular triglycerides and VLDL. The ability of insulin to suppress glucose and VLDL production in the fatty liver is impaired, resulting in mild hyperglycaemia and stimulation of insulin secretion, hypertriglyceridaemia, and low HDL cholesterol concentration. Damaged hepatocytes release increased amounts of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gammaglutamyltransferase (GGT), and overproduce C-reactive protein (CRP), fetuin A, fibroblast growth factor 21 (FGF21), and coagulation factors, FVII–IX, FXI–XII, and FGF21.
- The pathogenesis of nonalcoholic fatty liver disease (NAFLD). The pathogenesis of NAFLD involves the abnormal accumulation of free fatty acids, oxidative stress, endoplasmic reticulum (ER) stress, and a proinflammatory state in the liver. The percentage shown along the arrow indicates the prevalence of the pathogenesis leading to the next stage of NAFLD. Hallmarks and important features of each stage of NAFLD are indicated. Insulin resistance is an important pathological factor for the development of hepatic steatosis (a benign stage of NAFLD), presumably due to the induction of hepatic de novo lipogenesis as well as lipolysis of adipose tissue. Key enzymes involved in these processes are indicated (in pink box). Changes in the profile of adipokines and cytokine, dysbiosis of gut microbiota, hepatic oxidative stress/inflammation, and endoplasmic reticulum ER stress are regarded as the “multiple parallel hits” of the pathogenesis of NASH from hepatic steatosis. Key factors involved in the pathogenesis are indicated (in orange box). SREBP1: sterol regulatory element-binding protein-1; ACC: acetyl-CoA carboxylase; FAS: fatty acid synthase; ATGL: adipose triglyceride lipase; HSL: hormone-sensitive lipase; GI tract: gastrointestinal tract; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; ROS: reactive oxygen species; ER: endoplasmic reticulum; PDGF: platelet-derived growth factor; TGF-β: transforming growth factor-β; ECM: extracellular matrix.
- Fibrogenesisin esas prensibi hepatositlerin nekroz veya apoptozu ile başlar ve hepatik uydu hücrelerinin inflamasyona bağımlı aktivasyou ve miyofibroblastlara dönüşümleri ile devam eder ve ECM’in ekspresyonu ve sekresyonunun artması ve matriks birikimi ile beraber fibroza neden olur. Miyofibroblastların oluşumu siroz için ön koşul sayılır. Yeni patojenik mekanizmalar zedelenmiş KC dokusundaki kemik iliği kökenli hc.lerin (fibrosit) akımı dolaşımdaki monositler ve onların TGF-B farklılaşması sonucu oluşan fibroblastların oluşumunu düşündürür. Bir başka yeni bir mekanizma safra kanallarının epitel hc.lerinin epitelial-mezanşimal geçişidir. epithelial–mesenchymal transition (EMT). Bu mekanizmalar sayesinde hasarlı KC’de miyofibroblast havuzunu büyütür. En önemli fibrogenik aracılar TGF-B: transforming growth factor-𝛽, Platelet-derived growth factor: PDGF, IGF: insülin benzeri büyüme faktörü, endotelin-1 ve ROS dir.
- İnsanlarda sayıları bini geçen, protein kodlamayan ve gen ifadesini kontrol eden, yaklaşık 20- 23 nükleotit uzunluğunda tek iplikçikli RNA molekülleridir. Bu miRNA'ler uzunlukları küçük olduğundan mRNA ların ribozom bağlanma bölgelerinin civarına bağlanarak o mRNA'nın üreteceği proteinin sentezlenmesini engellerler. MicroRNAs are small (21–23 nucleotides), non-coding, highly conserved endogenous RNAs that regulate gene expression at the post-transcriptional level. miRNAs are important post-transcriptional regulators of gene expression, and the dysregulation of miRNAs is involved in various biological processes in the liver, including lipid homeostasis, inflammation, apoptosis, and cell proliferation. Recently, a number of studies have described the association between miRNAs and NAFLD progression and have shown that circulating miRNAs reflect histological changes in the liver. Four miRNAs (miR-340-5p, miR-484, miR-574-3p, and miR-720) were discovered to be involved in liver damage and tumorigenesis, and two miRNAs (miR-125a-5p and miR-182) were found to be dysregulated in earlystage NAFLD. Accordingly, miRNA profiles were differentially expressed in different NAFLD stages, thus suggesting that different pathological changes involve diverse miRNAs
- NAYK insüline dirençli obezlerde yaygın olarak görünmesine rağmen, bazen de insüline dirençli non obez bireylerde de metabolik sondromdan dolayı görülmesinin yanında, NAYK’in en az 2 tane genetik formu mevcuttur. Adiponutrin is a triacylglycerol lipase that mediates triacylglycerol hydrolysis in adipocytes. The encoded protein, which appears to be membrane bound, may be involved in the balance of energy usage/storage in adipocytes. The rs738409 variant has been reported to be associated with fibrosis. A number of studies have reported that rs738409 is also a risk factor for cirrhosis. Effects of TM6SF2 genetic variations. TM6SF2 plays a role in VLDL export from liver to serum which results in increased serum lipids and myocardial infarction, and decreased risk of liver steatosis. From Kahali et al[67], used by permission of the copyright holder. Chol: Cholesterol; LDL: Low-density lipoprotein cholesterol; IHTG: Intrahepatic triglyceride; NASH: Nonalcoholic steatohepatitis; TG: Triglyceride; VLDL: Very low-density lipoprotein.
- a | Marked steatosis without inflammation, hepatocyte injury (ballooning) or fibrosis. Steatosis is concentrated in acinar zone 3, the microcirculatory unit through which blood exits the liver around the terminal hepatic venule (in circle) and shows sparing of the periportal, zone 1 hepatocytes, the microcirculatory unit through which portal and systemic blood enter and mix. This is the adult pattern of nonalcoholic fatty liver disease (NAFLD) (trichrome staining). b | Steatohepatitis with marked steatosis (S), ballooning (B), lobular and portal inflammation (I) and extensive bridging fibrosis (haematoxylin and eosin staining). c | Fibrosis in the perisinusoidal spaces of zone 3 is detected by trichrome stain; bridging fibrosis (arrow) is noted between two central veins. Hepatocytes with steatosis are seen, but no ballooned hepatocytes are present. d | Nonalcoholic steatohepatitis (NASH) with cirrhosis, but no active lesions remain. One would only know this was a case of NASH-related cirrhosis by having had a prior biopsy with the diagnosis of active NASH. e | Hepatocellular carcinoma after the development of NASH and cirrhosis.
- Preeclampsia: gebeliğin ikinci yarısında gelişebilen hipertansiyon ve proteinüri ile kendisini gösteren rahatsızlık. Hypothesis illustrating the possible role of fetal and maternal MTP mutations in developing AFLP. Carrying an LCHAD deficient fetus (A) is the major determining factor in the development of maternal illness. Hepatotoxic metabolites produced by the fetus and/or placenta may cause liver disease in the obligate heterozygous mother when combined with the metabolic stress of the third trimester. Environmental stress (B) may lead to the further accumulation of toxic metabolites in the genetically susceptible mother causing maternal liver disease. LCHAD, long-chain 3-hydroxyacyl-CoA dehydrogenase; AFLP,acute fatty liver of pregnancy; MTP, mitochondrial trifunctional protein. (From Ibdah. World J Gastroenterol 2006;12:7397-404 [15]).
- Although radiologic assessment of NASH has improved, no radiologic method can detect a difference between NASH and NAFLD. Hepatik inflamasyonun öngörülmesndeki TNF-α, IL-6, CRP, Pantraxin, Ferritin, SPEA, ve sRAGE gibi temsili göstergelerin önerilmesine rağmen bunların kapsamlı bir şekilde doğrulanmasına ihtiyaç vardır. NASH tanısı açısından şimdiye kadar üzerinde en çok çalışılan tek bir test Sitokeratin-18'dir. hepatosit apoptoz belirteci olan CK-18 fragmanı, normal veya basit steatoza göre anlamlı dercede artan NASH’i öngörüyor.
- Proposed model of perturbations occurring in nonalcoholic fatty liver disease (NAFLD) iron homeostasis. A: Regulation of iron homeostasis under physiologic conditions. The amount of iron absorbed via duodenal enterocytes is tightly regulated by hepcidin according to body iron demands; hardly any iron deposits are found in the liver. B: Summary of changes in iron metabolism observed in NAFLD without iron overload. Low expressions of ferroportin-1 (FP-1) and hemojuvelin (HJV) are characteristic of NAFLD, even in the absence of iron accumulation; however, because no excess iron is deposited in the liver, hepcidin and consecutively duodenal FP-1 expressions are similar to those in control subjects. C: Changes in iron homeostasis in NAFLD with iron accumulation. Iron accumulates in NAFLD in association with significantly increased local and systemic mediators of inflammation, such as tumor necrosis factor- (TNF- ), which most likely originates from expanding adipose tissues. Iron is progressively retained mainly because of impaired iron export from liver cells via cytokine–mediated down-regulation of ferroportin. Hepatic iron accumulation stimulates hepcidin formation, which results in the blockage of duodenal iron uptake to compensate for liver iron overload. DMT-1, divalent metal transporter-1.
- Abstract Zinc deficiency is one of the most consistent nutritional/biochemical observations in alcoholic liver disease (ALD). The objectives of our research are to determine how alcohol interferes with cellular zinc homeostasis and if zinc deficiency is a causal factor in the development of ALD. Metallothionein (MT) is a major protein responsible for cellular zinc homeostasis. MT-transgenic (MT-TG) mice with hepatic overexpression of MT and elevation of zinc level were resistant to ethanol-induced liver injury. MT-knockout (MT-KO) mice with a reduction of hepatic zinc were more susceptible to alcohol toxicity. However, zinc treatment also provided beneficial effects on alcohol hepatoxicity in MT-KO mice, suggesting a MT-independent action. Dietary zinc supplementation normalized hepatic zinc level and attenuated the pathological changes in the liver of mice chronically fed alcohol. Several mechanisms were involved in zinc action against alcoholic cytotoxicity. Zinc enhanced cellular antioxidant capacity and corrected alcohol metabolic switch from alcohol dehydrogenase to cytochrome P4502E1. Zinc attenuated cytokine production and TNF- receptor- and Fas-mediated cell death pathways. Zinc restored activities of hepatocyte nuclear factor-4 (HNF-4 ) and peroxisome proliferation activator- (PPAR- ), and enhanced hepatic fatty acid -oxidation and lipid secretion. Hepatoma cell cultures showed that zinc deprivation induces lipid accumulation via inactivating HNF-4 and PPAR- . These results suggest that alcohol exposure interferes with hepatic zinc homeostasis, leading to cellular zinc deprivation. Inactivation of zinc proteins due to zinc release is likely an important molecular mechanism in the pathogenesis of ALD.
- Summary of the potential stimuli that may affect iron homeostasis in non-alcoholic fatty liver disease. Both, increasing and decreasing stimuli have been reported in non-alcoholic fatty liver disease and it appears likely that the net balance of these frequently counteracting forces fially determines the iron phenotype in the individual. Patterns of iron deposition may also be linked to distinct clinical consequences. IL-6: Interleukin 6; TNF-a: Tumor necrosis factor-a; LPS: Lipopolysaccharide; ER: Endoplasmatic reticulum; A1AT: α-1-antitrypsin; PPARGC1A: Peroxisome proliferator-activated receptor gamma coactivator 1-a; TMPRSS6: Transmembrane protease, serine 6; ESLD: End-stage liver disease; EGF: Epidermal growth factor; PDGF-BB: Platelet derived growth factor BB.
- Summary of how iron excess and low copper availability may affect whole body glucose and lipid homeostasis. Iron excess may promote insulin resistance in the liver, muscle and adipose tissue. Iron may increase ER and oxidative stress whereas low copper is potentially associated with an impaired antioxidant defence. These factors may result in the propagation of inflmmation, firogenesis and hepatocarcinogenesis. TNF-α: Tumor necrosis factor-α; ER: Endoplasmatic reticulum; FFA: Free fatty acid; VAT: Visceral adipose tissue; AT: Adipose tissue.
- Summary of mechanisms that lead to insulin resistance in heart failure or in the metabolic syndrome. Signaling events in skeletal muscle, liver, adipose tissue, and brain (not shown) impair insulin signaling in each respective organ leading to metabolic perturbations as illustrated, which alter the systemic milieu in ways that may adversely affect cardiac structure and function.
- Gábor Firneisz Non-alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age? July 21, 2014| Volume 20| Issue 27/ 9072-9089.