Towards a Better Understanding of Non-Alcoholic Fatty Liver Disease in 2018 Update on pathogenesis of Non-alcoholic fatty liver disease 전대원한양대학교의과대학내과 Dae Won Jun Department of Internal Medicine, Hanyang University, Seoul, Korea The pathophysiology of nonalcoholic fatty liver disease (NAFLD) has not yet been elucidated. Until now lipotoxicity hypothesis that hepatocyte apoptosis induced by excessive fat is explained as the basis of pathophysiology of NAFLD. Lipotoxicity has been seemed to be results from Two hits hypothesis. First Hit developed from intrahepatic fat accumulation, which is often associated with obesity and diabetes. Second Hit means that increases the susceptibility of hepatocytes apoptosis to secondary damage from endoplasmic reticulum stress. 'Two-Hit' hypothesis now fade out, as it is inadequate to explain the diverse phenotype of NAFLD. For example, presence of NASH does not correlate with the severity of steatosis. Lipotoxic mediators level (free fatty acid, ceramide ceramides, free cholesterol, diacyl-glycerol and phospholipids) do not correlated with progression of NAFLD. Anti-oxidative strategy or medication showed modest effects on NASH. Anti-apoptosis treatment showed modest effects on NAFLD. The Multi-Hit theory now take place in main hypothesis. Sublethal damage of hepatocyte, extracelluar vesicles, cell adaptation, genetic, epigenetic factors, and sarcopenia affect NAFLD pathogenesis. In this issue, we will discuss with several emerging pathophysiological mechanisms that are currently under the spotlight beyond the lipotoxicity. Key words: Non-alcoholic fatty liverl Lipotoxicity, Sarcopenia; Genetic 서 론 비알코올지방간질환의유병율은약 25% 정도를차지하고있다. 1 비알코올지방간질환은비만, 당뇨및심혈관계질환과높은연관성을보이며, 동시에당뇨및심혈관계질환발생의독립적인위험인자이다. 비알코올지방간질환의병태생리는아직명확하게밝혀진것은아니지만, 비만또는당뇨등과같은질환에의한간내지방이축적이되고이후간내과다하게축적된지방을처리하기위하여소포체 (endoplasmic reticulum) 에스트레스가발생되고, 결국과다한스트레스에의하여간세포의사멸 (apoptosis) 가유발된다는이른바 지방독성가설 (lipotoxicity theory) 가병태생리의근간으로설명되고있다. 2 그러나비알코올 www.kasl.org 11
2018 대한간학회추계 Single Topic Symposium 지방간질환은임상표현형이매우다양하여, 하나의병태생리로설명될수없으며매우다양한원인이병태생 리에작용을할것으로생각된다. 본연제에서는지방독성가설이외에최근각광을받는몇가지중요한 병태생리에대하여논하고자한다. 지방독성 (Lipid toxicity) 지방에의한세포의손상의기전은주로간내과다하게증가한지방산의생산에따른소포체 (endoplasmic reticulum) 에스트레스가발생되며이로인하여간세포의사멸이유도된다는것이다. 최근에는지방산에의한간세포 (hepatocyte) 의사멸이외에지방간에의하여단핵구 (monocyte) 의활성화, 특히전신에있는단핵구활성화를통하여간내단핵구의침윤및단핵구의성상의변화 (polarization) 가병태생리에중요함이밝혀졌다. 간세포와단핵구의활성화와세포사멸을유도하는인자는전통적으로알려진유리지방산 (free fatty acid) 이외에도 ceramides, free cholesterol, diacyl-glycerol and phospholipids 가중요한역할을한다고알려져있다. 3 그러나지방간이있는사람에서모두지방간염이발생되는것은아니며, 혈중또는간내유리지방산의농도와간내염증의정도와도차이가있다. 또한간내염증이심한경우에도간내섬유화는심하지않은경우가있어 lipotoxicity로비알코올지방간발생을모두설명하기는어렵다. 최근연구들은 lipotoxicity는비알코올지방간질환의발생에매우중요한필요조건이지만충분하지는않다고설명하고있으며, 비알코올지방간질환에서과다한 toxic lipid mediator 에의한간세포스트레스및다양한염증세포의자극이후에세포의반응, extracellular vesicle, 유전적요인, 면역반응등이보다중요할것으로생각된다. 4 세포외소낭 (extracellular vesicle) Extracellular vesicle (EV) 은크기와구성에있어다양하게분류할수있다. 세포외소낭은엑소좀 (exosomes), 미소낭포 (microvesicles), 자멸소체 (apoptotic bodies) 로나뉠수있다. 자멸소체는직경이 1 μm가넘고미소낭포는직경이 100-1,000 nm이며, 엑소좀은직경이 40-100 nm로가장작은막소낭이다. 세포외소낭 (EV) 은세포간의신호전달과세포의기능조절에매우중요한역할을한다고알려져있다. 최근연구에서 lysophosphatidylcholine (LPC) 자극은 stress kinase mixed lineage kinase 3 (MLK3) 활성화에의하여간세포에서다양한 EVs 배출을유도하여세포의증식과사멸에매우중요한역할을한다고알려져있다. 5 MLK3 활성화에의하여형성된 EVs은 C-X-C motif chemokine ligand 10 (CXCL10) 을유도한다고알려져있다. MLK3에의하여증가된 CXCL10은 TRAIL-R2, caspase 8, 및 caspase 3를활성화시켜결국 Rho-associated kinase1 (ROCK1) 을활성화시킨다. ROCK1 은세포의형태유지, 이동에중요한 12 대한간학회 Korean Association for the Study of the Liver
전대원 Update on Pathogenesis cytoskeleton을유지하는데중요한역할하며세포이 EVs 형성에도중요한역할을한다. 전임상실험에서 ROCK1 저해제는 EVs을감소시키고동물모델에서지방독성에의한간손상을억제하였다. 다양한자극에따라간세포에서는다양한종류의 EVs이분비가되며분비된 EVs은 CXCL family activation 이외에도신생혈관생성촉진, 6 mir-128-3p 매개간성상세포활성화에관려한다고알려져있다. 7 유전적요인 (Genetic factors) 유전적인요인은비알코올지방간질환발생에중요한역할을한다. Patatin-like phospholipase domain containing 3 (PNPLA3) 와 transmembrane 6 superfamily, member 2 (TM6SF2) 단일염기다형성 (Single Nucleotide Polymorphisoms, SNP) 은질환의발생및진행에영향을미친다고알려져있다. PNPLA3는중성지방과레티노이드대사를조절하는리파아제 (lipase) 의발현을조절한다. PNPLA3 단일염기다형성은간내지방량, 간내염증및간내섬유화와연관성이있을뿐만아니라알코올과연관된간질환과만성 C형간염환자에서간질환의진행과도연관이있다. PNPLA3 단일염기다형성은인종간에차이가있는데아시아인과미국인디언에게많으며서양인과흑인에게는적다고알려져있다. TM6SF2 은간세포에서 VLDL 분비를촉진시켜지방간발생에보호효과가있다. 그러나심혈관계질환발생의위험인자로알려져있다. 비알코올지방간에의한간경변질환에서유전적인요인이약절반가량영향을미친다고알려져있다. 8 비알코올지방간질환은유전자의염기서열이바뀌지않아도후생유전학적요인 (epigenetic factor) 에의하여염색질구조의변화를일으키거나염기서열의변화나신호개시없이유전자의발현양상을변화시킴으로써발생이될수있다. 후생유전학적변화는주로 DNA methylation, histone modifications 및 micrornas 등의조절을통하여이루어진다. 동물실험에서임신기간동안과잉영양또는영양결핍을유도하는경우태어난쥐에서당뇨및비만의발생이높다고알려져있다. 이는염색체단백질인히스톤이 대사센터 (metabolic sensor)" 로작용하기때문으로추정되며메틸기전달이중요한역할을한다고알려져있다. 일탄소대사 (one-carbon metabolism) 는엽산 (folate) 과메티오닌 (methionine) 을통하여단백질, 지질의대사및산화경로및후성유전학메틸기전달을조절하는대사과정을지칭한다. 일탄소대사 (one-carbon metabolism) 는메틸기를제공하는과정인 transmethylation pathway 와 glutathione(gsh) 을생성하는 transsulfuration pathway로이루어진다. 일탄소대사는간에서많이일어나며메티오닌은비알코올지방간질환의발생에매우중요한역할을하고있다는것은주지의사실이다. 메틸기탄소는주로우리가먹는음식으로부터제공받게되며일탄소대사과정을거쳐핵산생합성, ROS 관련조효소인 NADPH 생성, 메틸화에필요한 S-adenosylmethionine (SAM) 생성, 인지질생합성을조절한다. www.kasl.org 13
2018 대한간학회추계 Single Topic Symposium 근감소증과근감소형비만 (Sarcopenia and Sarcopenic obesity) 근육의기능은지방간염의발생과연관이있으며동시에반대의경우도성립한다. 근감소증과비알코올지방간질환과의연관성에대하여여러개의연구가보고되었다. 9-13 그러나근감소증의정의에따라근감소증과지방간의연관성은다르게보고되고있다. 근감소증의정의를근육량을체중또는 BMI로나눈값을이용한경우는근감소증과지방간은양의상관관계를보였으나, 11,13 근육량을신장으로나누어정의를하는경우근감소증과지방간유병율은역의상관관계를보였다. 12 BMI는지방간및근감소증에매우중요한요인으로근감소증의정의를어떻게하는가에따라연구결과가다르게보고되고있다. 이러한점은근육의양과질이감소하는 true sarcopenia 와상대적으로근육량이적은 sarcopenic obesity를구별하지못하여발생되는현상으로판단된다. 향후비알코올지방간질환에서근육량감소를정의하기위하여통일된기준과함께근육의질을평가하는방법 ( 악력또는보행속도 ) 등이함께고려되어야할것이다. REFERENCES 1. Jeong EH, Jun DW, Cho YK, Choe YG, Ryu S, Lee SM, et al. Regional prevalence of non-alcoholic fatty liver disease in Seoul and Gyeonggi-do, Korea. Clin Mol Hepatol 2013;19:266-272. 2. Hirsova P, Gores GJ. Death Receptor-Mediated Cell Death and Proinflammatory Signaling in Nonalcoholic Steatohepatitis. Cell Mol Gastroenterol Hepatol 2015;1:17-27. 3. Hirsova P, Ibrahim SH, Gores GJ, Malhi H. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res 2016;57:1758-1770. 4. Ibrahim SH, Hirsova P, Gores GJ. Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation. Gut 2018;67:963-972. 5. Ibrahim SH, Hirsova P, Tomita K, Bronk SF, Werneburg NW, Harrison SA, et al. Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology 2016;63:731-744. 6. Povero D, Eguchi A, Niesman IR, Andronikou N, de Mollerat du Jeu X, Mulya A, et al. Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require Vanin-1 for uptake by endothelial cells. Sci Signal 2013;6:ra88. 7. Povero D, Panera N, Eguchi A, Johnson CD, Papouchado BG, de Araujo Horcel L, et al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via micrornas targeting PPAR-gamma. Cell Mol Gastroenterol Hepatol 2015;1:646-663 e644. 8. Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, et al. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology 2015;149:1784-1793. 9. Bhanji RA, Narayanan P, Allen AM, Malhi H, Watt KD. Sarcopenia in hiding: The risk and consequence of underestimating muscle dysfunction in nonalcoholic steatohepatitis. Hepatology 2017;66:2055-2065. 10. Peng TC, Wu LW, Chen WL, Liaw FY, Chang YW, Kao TW. Nonalcoholic fatty liver disease and sarcopenia in a Western population (NHANES III): The importance of sarcopenia definition. Clin Nutr 2017. 11. Hong HC, Hwang SY, Choi HY, Yoo HJ, Seo JA, Kim SG, et al. Relationship between sarcopenia and nonalcoholic fatty liver disease: the Korean Sarcopenic Obesity Study. Hepatology 2014;59:1772-1778. 12. Carey EJ, Lai JC, Wang CW, Dasarathy S, Lobach I, Montano-Loza AJ, et al. A multicenter study to define sarcopenia in patients with end-stage liver disease. Liver Transpl 2017;23:625-633. 14 대한간학회 Korean Association for the Study of the Liver
전대원 Update on Pathogenesis 13. Lee YH, Kim SU, Song K, Park JY, Kim DY, Ahn SH, et al. Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: Nationwide surveys (KNHANES 2008-2011). Hepatology 2016;63:776-786. www.kasl.org 15