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Nonalcoholic Fatty Liver Disease Progresses Into Severe NASH When Physiological Mechanisms of Tissue Homeostasis Collapse

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Nonalcoholic Fatty Liver Disease Progresses Into Severe NASH When Physiological Mechanisms of Tissue Homeostasis Collapse 182 Sookoian S, et al. , 2018; 17 (2): 182-186 OPINION March-April, Vol. 17 No. 2, 2018: 182-186 The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver Nonalcoholic Fatty Liver Disease Progresses into Severe NASH when Physiological Mechanisms of Tissue Homeostasis Collapse Silvia Sookoian,*,** Carlos J. Pirola*,*** * University of Buenos Aires, Institute of Medical Research A Lanari, Buenos Aires, Argentina. ** National Scientific and Technical Research Council (CONICET) - University of Buenos Aires, Institute of Medical Research (IDIM), Department of Clinical and Molecular Hepatology, Buenos Aires, Argentina. *** National Scientific and Technical Research Council (CONICET)-University of Buenos Aires, Institute of Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, Buenos Aires, Argentina. ABSTRACT Phenotypic modulation of NAFLD-severity by molecules derived from white (adipokines) and brown (batokines) adipose tissue may be important in inducing or protecting against the progression of the disease. Adipose tissue-derived factors can promote the pro- gression of NAFLD towards severe histological stages (NASH-fibrosis and NASHcirrhosis). This effect can be modulated by the release of adipokines or batokines that directly trigger an inflammatory response in the liver tissue or indirectly modulate related phenotypes, such as insulin resistance. Metabolically dysfunctional adipose tissue, which is often infiltrated by macrophages and crown-like histological structures, may also show impaired production of anti-inflammatory cytokines, which may favor NAFLD progression into aggressive phenotypes by preventing its protective effects on the liver tissue. Key words. NAFLD. NASH. Fibrosis. Metabolic stress. 2-4 Opinion Article on the MS published in ease, suggests the presence of an even more intricate the Journal of Clinical Investigation entitled: network of pathogenic mechanisms that not only interact Hepatic neuregulin 4 signaling defines an with each other but also increase the chances of having a endocrine checkpoint for steatosis-to-NASH progression. more dramatic and severe phenotype. In this regard, the cross-talk between NAFLD and adipose tissue has gained Nonalcoholic fatty liver disease (NAFLD) is regarded particular attention of researchers and practitioners be- as the most prevalent chronic liver disease worldwide.1 cause cytokines derived from either white fat-WAT (adi- Although the disease is considered benign and having a pokines) or brown fat-BAT (batokines) play a remarkable relatively good prognosis when the diagnosis is made at role in the development and maintenance of NAFLD dis- earlier histological stages, the progression into severe ease severity. Figure 1 illustrates the concept of phenotyp- clinical forms, including nonalcoholic steatohepatitis ic modulation of NAFLD severity by molecules derived (NASH), NASH-fibrosis and NASH-cirrhosis, imposes from adipose tissue that act as paracrine and endocrine tremendous medical challenges.1 For these reasons, exten- hormones.5,6 sive body of research aimed at the search for factors and or Pathways involved in organ damage and injury, includ- causes that modify the natural history of NAFLD is cur- ing cellular apoptosis or other process associated with cell rently being conducted. death, as well as persistent tissue inflammation and the The complexity of the NAFLD-associated clinical pic- consequent fibrogenesis, are all triggered by multiple fac- ture, specifically the association with co-morbidities such tors, including genetic predisposition and epigenetic as type 2 diabetes (T2D),1 obesity and cardiovascular dis- modifiers.7-9 Nevertheless, the exact mechanism/s that Manuscript received: January 23, 2018. Manuscript accepted: January 23, 2018. DOI:10.5604/01.3001.0010.8631 NFLD Progresses into Severe NASH. , 2018; 17 (2): 182-186 183 FFiiguregure 11.. Phenotypic modulation of NAFLD-se- Adiponectin verity by molecules derived from white (adipok- SFRP5 ines) and brown (batokines) adipose tissue by FGF21 FGF21 inducing or protecting against the progression of NRG4 NRG4 the disease. Adipose tissue-derived factors can UCP1 promote the progression of NAFLD towards se- TNFα vere histological stages (NASH-fibrosis and NASH- IL6 IL6 cirrhosis). This effect can be modulated by the Resistin IGF1 release of adipokines that directly trigger an in- IL1 White adipose tissue Brown flammatory response in the liver tissue or indirectly MCP-1 adipose tissue NASH modulate related phenotypes, such as insulin re- PAI1 (BAT) RBP4 sistance (up-arrows). Metabolically dysfunctional Visfatin adipose tissue, which is often infiltrated by macro- Leptin phages and crown-like histological structures, may Chemerin NASH - also show impaired production of anti-inflammato- Omentin NAFL fibrosis ry adipokines, which may favor NAFLD progres- sion into aggressive phenotypes by preventing its protective effects on the liver tissue (down-ar- rows). SFRP5: secreted frizzled-related protein 5. NASH - NASH - UCP1: uncoupling protein 1. FGF21: fibroblast cirrhosis growth factor 21. TNFα: tumor necrosis factor α. IL1 and IL6: interleukin 1 and 6. MCP-1: mono- cyte chemotactic protien-1. promote the transition of NAFL (nonalcoholic fatty liver) Considering the aforementioned findings collectively, to NASH remain(s) elusive. it is plausible to hypothesize that NAFLD progression is a Guo, et al. recently reported the role of Neuregulin 4 process in which physiological mechanisms of tissue (Nrg4), an adipose tissue-enriched endocrine factor, in the homeostasis collapse. There is compelling evidence from development of NASH.10 Specifically, the authors used a human studies supporting this hypothesis. For instance, mouse model of high-fat-fructose diet-induced NASH ballooning degeneration —a hallmark histological feature that recapitulates main histological features of human of NAFLD severity and NASH progression— is associat- NASH.10 Key molecular findings associated with the pres- ed with down-regulation of liver HSP27 gene and protein ence of NASH in mice were: expression.11 HSP27 is a member of the heat shock family of proteins also known as stress-responsive protein 27. • Cell death, which was associated with both increased Furthermore, NASH development is associated with mi- phosphorylation of the member of the MAP-kinase tochondrial dysfunction, increased mitochondrial DNA family JNK1/2 and reduced protein levels of the inhib- (mtDNA) genetic diversity, down-regulation of liver ex- itor of apoptotic and necroptotic cell death c-FLIPL pression of genes of the oxidative phosphorylation (OX- (Caspase 8 and FADD-Like Apoptosis Regulatory Pro- PHOS) chain, and aberrant patterns of mtDNA tein, CFLAR), and methylation.7,8,12,13 • Significantly decreased mRNA expression of Nrg4 in The first question that immediately emerges is what epididymal WAT and BAT.10 factor/s trigger this complex picture? Robust evidence supports the notion that NAFLD Subsequent Nrg4 gain- and loss-of-function studies in severity is associated with metabolic stress. In fact, it mouse models showed that restoration of Nrg4 signaling has been linked with increased transamination reactions protects animals from NASH; specifically, Nrg4 signaling that would promote coping with the liver metabolic de- protects animals from stress-induced cell death through rangement.14 This, in turn, leads to changes in the interaction with c-FLIP.10 Notably, genes associated with amounts of amino acids released into the circulation, fibrogenesis (Col1a1, Acta2, Tgfb1, and Mmp13) and inflam- particularly in pathways related to glutamic acid.13,14 As mation (Tnfa, Il1b, Il12b, Nos2, Ccl2, Ccl5, and Adgre1) were reported recently, glutaminolysis controls accumula- upregulated in mice lacking Nrg4, suggesting that Nrg4 de- tion of myofibroblast hepatic stellate cells.15 Deregulat- ficiency exacerbated liver inflammation and fibrosis fol- ed liver metabolism also leads to aberrant patters of lowing NASH-diet feeding.10 It is worth noting that a hedgehog signaling16,17 and insufficient ketogenesis, similar profile in human NAFLD was described by our which result in extensive hepatocyte injury and inflam- research group.2 mation, decreased glycemia, and deranged hepatic TCA 184 Sookoian S, et al. , 2018; 17 (2): 182-186 (tricarboxylic acid) cycle intermediate concentra- tor) and Srebp1c (sterol regulatory element binding tran- tions.14,18 scription factor 1) in a cell-autonomous manner.20 The second, and even more difficult to answer ques- Data yielded by human studies is not only insufficient, tion is why a brown fat-derived secreted factor is impor- but is also inconclusive. Kang, et al. found that the circulat- tant in maintaining liver tissue homeostasis? ing NRG4 levels are increased in patients with type 2 dia- It is well known that systemic metabolic homeostasis betes and positively correlate with serum glucose level, is regulated by the “in concert” action of a myriad of tis- HOMA-IR, and serum triglycerides;21 however, opposite sue-derived factors, which originate from different results were reported by Yan, et al.22 Controversial evi- sources, including adipose tissue, gut, muscle, liver and dence has also been derived from studies of gestational di- bone. These hormones / growth factors / bioactive mole- abetes.23,24 For example, Cai, et al. reported that NRG4 cules basically sense global metabolism
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