bims-nastce Biomed News
on NASH and T cells
Issue of 2021–08–08
fourteen papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma.
  2. Extracellular Vesicles in Non-alcoholic Fatty Liver Disease and Alcoholic Liver Disease.
  3. Intestine-Liver Cross-talk in Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease.
  4. The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma.
  5. Microbiome-targeted diets that alter immune status.
  6. The Gut Microbiota-Derived Immune Response in Chronic Liver Disease.
  7. Prevention of NAFLD-associated HCC: role of lifestyle and chemoprevention.
  8. The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target.
  9. CD8+ T Cell Exhaustion in Cancer.
  10. Suppressor CD4+ T cells expressing HLA-G are expanded in the peripheral blood from patients with acute decompensation of cirrhosis.
  11. Effects of Morbid Obesity and Metabolic Syndrome on the Composition of Circulating Immune Subsets.
  12. Hyperlipidemia induced metabolic changes in regulatory T cells result in altered function.
  13. Diet-Induced Models of Non-Alcoholic Fatty Liver Disease: Food for Thought on Sugar, Fat, and Cholesterol.
  14. Hepatic mitochondrial SAB deletion or knockdown alleviates diet induced metabolic syndrome, steatohepatitis and hepatic fibrosis.
  1. Dig Liver Dis. 2021 Jul 31. pii: S1590-8658(21)00375-3. [Epub ahead of print]
    Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma.
    Hui Li.
      Intercellular crosstalk among various liver cells plays an important role in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Capillarization of liver sinusoidal endothelial cells (LSECs) precedes fibrosis and accumulating evidence suggests that the crosstalk between LSECs and other liver cells is critical in the development and progression of liver fibrosis. LSECs dysfunction, a key event in the progression from fibrosis to cirrhosis, and subsequently obstruction of hepatic sinuses and increased intrahepatic vascular resistance (IHVR) contribute to development of portal hypertension (PHT) and cirrhosis. More importantly, immunosuppressive tumor microenvironment (TME), which is closely related to the crosstalk between LSECs and immune liver cells like CD8+ T cells, promotes advances tumorigenesis, especially HCC. However, the connections within the crosstalk between LSECs and other liver cells during the progression from liver fibrosis to cirrhosis to HCC have yet to be discussed. In this review, we first summarize the current knowledge of how different crosstalk between LSECs and other liver cells, including hepatocytes, hepatic stellate cells (HSCs), macrophoges, immune cells in liver and extra cellular matrix (ECM) contribute to the physiological function and the progrssion from liver fibrosis to cirrhosis, or even to HCC. Then we examine current treatment strategies for LSECs crosstalk in liver fibrosis, cirrhosis and HCC.
    Keywords:  Cirrhosis; Crosstalk; HCC; LSECs; Liver fibrosis
    DOI:  https://doi.org/10.1016/j.dld.2021.07.006
  2. Front Physiol. 2021 ;12 707429
    Extracellular Vesicles in Non-alcoholic Fatty Liver Disease and Alcoholic Liver Disease.
    Dongqing Wu, Huaqing Zhu, Hua Wang.
      As the largest vital solid organ in the body, liver is consisting of multiple types of cells including hepatocytes, Kupffer cell, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), and other immune cells. The communication between these cells is critical in maintaining liver function homeostasis, and dysregulation of such communication contributes to the pathogenesis of various liver diseases. Extracellular vesicles (EVs), including exosomes and ectosomes, act as important mediators of cell-to-cell communication. EVs can be produced and uptaken by a wide range of cells including all types of cells in the liver. Growing evidences show that EVs are involved in the development of liver diseases, especially non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). In this review, we will summarize recent advance in how EVs production are altered in NAFLD and ALD and how the changes of EVs quantity and cargos influence the progression of these diseases. The therapeutic and diagnostic potential of EVs in NAFLD and ALD will be also discussed in this review.
    Keywords:  alcoholic liver disease; biomarker; extracellular vesicles; non-alcoholic fatty liver disease; pathogenesis
    DOI:  https://doi.org/10.3389/fphys.2021.707429
  3. Metabolism. 2021 Jul 31. pii: S0026-0495(21)00144-X. [Epub ahead of print] 154844
    Intestine-Liver Cross-talk in Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease.
    Margaux Nawrot, Simon Peschard, Sophie Lestavel, Bart Staels.
      Type 2 diabetes (T2D) and Non-Alcoholic Fatty Liver Disease (NAFLD) are pathologies whose prevalence continues to increase worldwide. Both diseases are precipitated by an excessive caloric intake, which promotes insulin resistance and fatty liver. The role of the intestine and its crosstalk with the liver in the development of these metabolic diseases is receiving increasing attention. Alterations in diet-intestinal microbiota interactions lead to the dysregulation of intestinal functions, resulting in altered metabolite and energy substrate production and increased intestinal permeability. Connected through the portal circulation, these changes in intestinal functions impact the liver and other metabolic organs, such as visceral adipose tissue, hence participating in the development of insulin resistance, and worsening T2D and NAFLD. Thus, targeting the intestine may be an efficient therapeutic approach to cure T2D and NAFLD. In this review, we will first introduce the signaling pathways linking T2D and NAFLD. Next, we will address the role of the gut-liver crosstalk in the development of T2D and NAFLD, with a particular focus on the gut microbiota and the molecular pathways behind the increased intestinal permeability and inflammation. Finally, we will summarize the therapeutic strategies which target the gut and its functions and are currently used or under development to treat T2D and NAFLD.
    Keywords:  NAFLD; intestine-liver cross-talk; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.metabol.2021.154844
  4. Gut. 2021 Aug 02. pii: gutjnl-2021-325288. [Epub ahead of print]
    The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma.
    Bernd Heinrich, E Michael Gertz, Alejandro A Schäffer, Amanda Craig, Benjamin Ruf, Varun Subramanyam, John C McVey, Laurence P Diggs, Sophia Heinrich, Umberto Rosato, Chi Ma, Chunhua Yan, Ying Hu, Yongmei Zhao, Tsai-Wei Shen, Veena Kapoor, William Telford, David E Kleiner, Merril K Stovroff, Harmeet S Dhani, Jiman Kang, Thomas Fishbein, Xin Wei Wang, E Ruppin, Alexander Kroemer, Tim F Greten, Firouzeh Korangy.
       OBJECTIVE: Hepatocellular carcinoma (HCC) represents a typical inflammation-associated cancer. Tissue resident innate lymphoid cells (ILCs) have been suggested to control tumour surveillance. Here, we studied how the local cytokine milieu controls ILCs in HCC.
    DESIGN: We performed bulk RNA sequencing of HCC tissue as well as flow cytometry and single-cell RNA sequencing of enriched ILCs from non-tumour liver, margin and tumour core derived from 48 patients with HCC. Simultaneous measurement of protein and RNA expression at the single-cell level (AbSeq) identified precise signatures of ILC subgroups. In vitro culturing of ILCs was used to validate findings from in silico analysis. Analysis of RNA-sequencing data from large HCC cohorts allowed stratification and survival analysis based on transcriptomic signatures.
    RESULTS: RNA sequencing of tumour, non-tumour and margin identified tumour-dependent gradients, which were associated with poor survival and control of ILC plasticity. Single-cell RNA sequencing and flow cytometry of ILCs from HCC livers identified natural killer (NK)-like cells in the non-tumour tissue, losing their cytotoxic profile as they transitioned into tumour ILC1 and NK-like-ILC3 cells. Tumour ILC composition was mediated by cytokine gradients that directed ILC plasticity towards activated tumour ILC2s. This was liver-specific and not seen in ILCs from peripheral blood mononuclear cells. Patients with high ILC2/ILC1 ratio expressed interleukin-33 in the tumour that promoted ILC2 generation, which was associated with better survival.
    CONCLUSION: Our results suggest that the tumour cytokine milieu controls ILC composition and HCC outcome. Specific changes of cytokines modify ILC composition in the tumour by inducing plasticity and alter ILC function.
    Keywords:  hepatocellular carcinoma; immune response; immunology; immunoregulation; liver immunology
    DOI:  https://doi.org/10.1136/gutjnl-2021-325288
  5. Nat Rev Gastroenterol Hepatol. 2021 Aug 05.
    Microbiome-targeted diets that alter immune status.
    Caroline Barranco.
      
    DOI:  https://doi.org/10.1038/s41575-021-00509-2
  6. Int J Mol Sci. 2021 Aug 02. pii: 8309. [Epub ahead of print]22(15):
    The Gut Microbiota-Derived Immune Response in Chronic Liver Disease.
    Sung-Min Won, Eunju Park, Jin-Ju Jung, Raja Ganesan, Haripriya Gupta, Yoseph Asmelash Gebru, SatyaPriya Sharma, Dong-Joon Kim, Ki-Tae Suk.
      In chronic liver disease, the causative factor is important; however, recently, the intestinal microbiome has been associated with the progression of chronic liver disease and the occurrence of side effects. The immune system is affected by the metabolites of the microbiome, and diet is the primary regulator of the microbiota composition and function in the gut-liver axis. These metabolites can be used as therapeutic material, and postbiotics, in the future, can increase or decrease human immunity by modulating inflammation and immune reactions. Therefore, the excessive intake of nutrients and the lack of nutrition have important effects on immunity and inflammation. Evidence has been published indicating that microbiome-induced chronic inflammation and the consequent immune dysregulation affect the development of chronic liver disease. In this research paper, we discuss the overall trend of microbiome-derived substances related to immunity and the future research directions.
    Keywords:  chronic liver disease; gut microbiome; gut–liver axis; immune response
    DOI:  https://doi.org/10.3390/ijms22158309
  7. J Hepatol. 2021 Jul 30. pii: S0168-8278(21)01954-1. [Epub ahead of print]
    Prevention of NAFLD-associated HCC: role of lifestyle and chemoprevention.
    Naomi F Lange, Pompilia Radu, Jean-François Dufour.
      In many countries worldwide, the burden of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing and preventive strategies are needed to counteract this trend. This review provides an overview of the evidence on preventive strategies in NAFLD-associated HCC. We considered the impact of lifestyle factors such as weight loss, physical activity, smoking, dietary patterns and food items, including coffee and alcohol, on both HCC and NAFLD/NASH. Furthermore, evidence on chemopreventive treatments, including aspirin, anti-diabetic treatments and statins is summarized. The role of adjuvant therapies considered for tertiary prevention of HCC is briefly reviewed.
    Keywords:  Non-alcoholic fatty liver disease (NAFLD); Nonalcoholi steatohepatitis (NASH); aspirin; coffee; hepatocellular carcinoma (HCC); lifestyle; metformin; prevention; statins
    DOI:  https://doi.org/10.1016/j.jhep.2021.07.025
  8. Int J Mol Sci. 2021 Jul 29. pii: 8161. [Epub ahead of print]22(15):
    The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target.
    Takaomi Kessoku, Takashi Kobayashi, Kosuke Tanaka, Atsushi Yamamoto, Kota Takahashi, Michihiro Iwaki, Anna Ozaki, Yuki Kasai, Asako Nogami, Yasushi Honda, Yuji Ogawa, Shingo Kato, Kento Imajo, Takuma Higurashi, Kunihiro Hosono, Masato Yoneda, Haruki Usuda, Koichiro Wada, Satoru Saito, Atsushi Nakajima.
      The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10-20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut-liver axis in NAFLD pathogenesis and progression.
    Keywords:  endotoxin; gut permeability; leaky gut; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis
    DOI:  https://doi.org/10.3390/ijms22158161
  9. Front Immunol. 2021 ;12 715234
    CD8+ T Cell Exhaustion in Cancer.
    Joseph S Dolina, Natalija Van Braeckel-Budimir, Graham D Thomas, Shahram Salek-Ardakani.
      A paradigm shift in the understanding of the exhausted CD8+ T cell (Tex) lineage is underway. Originally thought to be a uniform population that progressively loses effector function in response to persistent antigen, single-cell analysis has now revealed that CD8+ Tex is composed of multiple interconnected subpopulations. The heterogeneity within the CD8+ Tex lineage is comprised of immune checkpoint blockade (ICB) permissive and refractory subsets termed stem-like and terminally differentiated cells, respectively. These populations occupy distinct peripheral and intratumoral niches and are characterized by transcriptional processes that govern transitions between cell states. This review presents key findings in the field to construct an updated view of the spatial, transcriptional, and functional heterogeneity of anti-tumoral CD8+ Tex. These emerging insights broadly call for (re-)focusing cancer immunotherapies to center on the driver mechanism(s) underlying the CD8+ Tex developmental continuum aimed at stabilizing functional subsets.
    Keywords:  CXCR3; PD-1/PD-L1; T cell exhaustion; T cell trafficking; cancer immunotherapy; co-stimulatory/inhibitory receptors; stem-like CD8+ T cells; tumor immunity
    DOI:  https://doi.org/10.3389/fimmu.2021.715234
  10. Gut. 2021 Aug 03. pii: gutjnl-2021-324071. [Epub ahead of print]
    Suppressor CD4+ T cells expressing HLA-G are expanded in the peripheral blood from patients with acute decompensation of cirrhosis.
    Wafa Khamri, Cathrin Gudd, Tong Liu, Rooshi Nathwani, Marigona Krasniqi, Sofia Azam, Thomas Barbera, Francesca M Trovato, Lucia Possamai, Evangelos Triantafyllou, Rocio Castro Seoane, Fanny Lebosse, Arjuna Singanayagam, Naveenta Kumar, Christine Bernsmeier, Sujit Mukherjee, Mark McPhail, Chris J Weston, Charalambos Gustav Antoniades, Mark R Thursz.
       OBJECTIVE: Identifying components of immuneparesis, a hallmark of chronic liver failure, is crucial for our understanding of complications in cirrhosis. Various suppressor CD4+ T cells have been established as potent inhibitors of systemic immune activation. Here, we establish the presence, regulation and mechanism of action of a suppressive CD4+ T cell subset expressing human leucocyte antigen G (HLA-G) in patients with acute decompensation of cirrhosis (AD).
    DESIGN: Flow cytometry was used to determine the proportion and immunophenotype of CD4+HLA-G+ T cells from peripheral blood of 20 healthy controls (HCs) and 98 patients with cirrhosis (28 with stable cirrhosis (SC), 20 with chronic decompensated cirrhosis (CD) and 50 with AD). Transcriptional and functional signatures of cell-sorted CD4+HLA-G+ cells were delineated by NanoString technology and suppression assays, respectively. The role of immunosuppressive cytokine interleukin (IL)-35 in inducing this population was investigated through in vitro blockade experiments. Immunohistochemistry (IHC) and cultures of primary human Kupffer cells (KCs) were performed to assess cellular sources of IL-35. HLA-G-mediated T cell suppression was explored using neutralising antibodies targeting co-inhibitory pathways.
    RESULTS: Patients with AD were distinguished by an expansion of a CD4+HLA-G+CTLA-4+IL-35+ immunosuppressive population associated with disease severity, clinical course of AD, infectious complications and poor outcome. Transcriptomic analyses excluded the possibility that these were thymic-derived regulatory T cells. IHC analyses and in vitro cultures demonstrate that KCs represent a potent source of IL-35 which can induce the observed HLA-G+ phenotype. These exert cytotoxic T lymphocyte antigen-4-mediated impaired responses in T cells paralleled by an HLA-G-driven downregulation of T helper 17-related cytokines.
    CONCLUSION: We have identified a cytokine-driven peripherally derived suppressive population that may contribute to immuneparesis in AD.
    Keywords:  immunology in hepatology; immunoregulation
    DOI:  https://doi.org/10.1136/gutjnl-2021-324071
  11. Front Immunol. 2021 ;12 675018
    Effects of Morbid Obesity and Metabolic Syndrome on the Composition of Circulating Immune Subsets.
    Leontine H Wijngaarden, Erwin van der Harst, René A Klaassen, Martin Dunkelgrun, T Martijn Kuijper, Mariska Klepper, Gisela Ambagtsheer, Jan N M IJzermans, Ron W F de Bruin, Nicolle H R Litjens.
      Morbid obesity is characterized by chronic, low-grade inflammation, which is associated with 'inflamm-aging'. The presence of metabolic syndrome (MetS) might accelerate this phenomenon of metaflammation. In this study, we assessed the effects of morbid obesity and MetS on the composition of a broad spectrum of immune cells present within the circulation. A total of 117 morbidly obese patients (MOP) without MetS (MetS-), 127 MOP with MetS (MetS+) and 55 lean controls (LC) were included in this study. Absolute numbers of T cell, B cell, NK cell and monocyte subsets were assessed within peripheral blood using flow cytometry. Both absolute cell numbers and proportion of cells were evaluated correcting for covariates age, body mass index and cytomegalovirus serostatus. Although the absolute number of circulating CD4+ T cells was increased in the MetS+ group, the CD4+ T cell composition was not influenced by MetS. The CD8+ T cell and B cell compartment contained more differentiated cells in the MOP, but was not affected by MetS. Even though the absolute numbers of NK cells and monocytes were increased in the MOP as compared to LC, there was no difference in proportions of NK and monocyte subsets between the three study groups. In conclusion, although absolute numbers of CD4+ and CD8+ T cells, B cells, NK cells and monocytes are increased in MOP, obesity-induced effects of the composition of the immune system are confined to a more differentiated phenotype of CD8+ T cells and B cells. These results were not affected by MetS.
    Keywords:  B cells; NK cells; T cells; metabolic syndrome; metaflammation; monocytes; morbid obesity
    DOI:  https://doi.org/10.3389/fimmu.2021.675018
  12. Eur J Immunol. 2021 Aug 07.
    Hyperlipidemia induced metabolic changes in regulatory T cells result in altered function.
    Michael Hyde, Jessamyn Bagley, Philip W Hinds, Philip Tsichlis, John Iacomini.
      Regulatory T cells (Tregs) play a critical role in maintaining self-tolerance and controlling inflammation. However, physiologically relevant conditions that alter Treg function and drive disease pathogenesis are poorly understood and few have been defined. We have previously shown that induction of hyperlipidemia in mice results in changes in Tregs that reduce their function. Here we set out to examine mechanisms by which hyperlipidemia alters Tregs. Using live-cell metabolic assays, we observed that induction of hyperlipidemia increases metabolism in Tregs but not conventional T cells. Increased metabolism resulted from preferential activation of the serine/threonine kinase Akt2 (PKBβ). Expression of a constitutively activated form of Akt2 in CD4 T cells was sufficient to increase glycolysis in Tregs and drive changes in Treg subsets. Induction of hyperlipidemia did not alter Treg metabolism in mice lacking Akt2. Activation of Akt2 was sufficient to drive production of inflammatory cytokines by Tregs. We suggest that hyperlipidemia alters Treg function through effects on metabolism via Akt2 activation thereby promoting plasticity and decreased function of FoxP3+ T cells. This article is protected by copyright. All rights reserved.
    Keywords:  Hyperlipidemia; Metabolism; Plasticity; Regulatory T cells
    DOI:  https://doi.org/10.1002/eji.202049149
  13. Cells. 2021 Jul 16. pii: 1805. [Epub ahead of print]10(7):
    Diet-Induced Models of Non-Alcoholic Fatty Liver Disease: Food for Thought on Sugar, Fat, and Cholesterol.
    James M Eng, Jennifer L Estall.
      Non-alcoholic fatty liver disease (NAFLD) affects approximately 1 in 4 people worldwide and is a major burden to health care systems. A major concern in NAFLD research is lack of confidence in pre-clinical animal models, raising questions regarding translation to humans. Recently, there has been renewed interest in creating dietary models of NAFLD with higher similarity to human diets in hopes to better recapitulate disease pathology. This review summarizes recent research comparing individual roles of major dietary components to NAFLD and addresses common misconceptions surrounding frequently used diet-based NAFLD models. We discuss the effects of glucose, fructose, and sucrose on the liver, and how solid vs. liquid sugar differ in promoting disease. We consider studies on dosages of fat and cholesterol needed to promote NAFLD versus NASH, and discuss important considerations when choosing control diets, mouse strains, and diet duration. Lastly, we provide our recommendations on amount and type of sugar, fat, and cholesterol to include when modelling diet-induced NAFLD/NASH in mice.
    Keywords:  NAFLD; NASH; cholesterol; dietary model; high-fat diet; liquid sugar; liver; solid sugar
    DOI:  https://doi.org/10.3390/cells10071805
  14. Hepatology. 2021 Jul 31.
    Hepatic mitochondrial SAB deletion or knockdown alleviates diet induced metabolic syndrome, steatohepatitis and hepatic fibrosis.
    Sanda Win, Robert W M Min, Jun Zhang, Gary Kanel, Brad Wanken, Yibu Chen, Meng Li, Ying Wang, Ayako Suzuki, Filbert W M Aung, Susan F Murray, Mariam Aghajan, Tin A Than, Neil Kaplowitz.
      The hepatic MAPK cascade leading to JNK activation has been implicated in the pathogenesis of nonalcoholic fatty liver /non-alcoholic steatohepatitis (NAFL/NASH). In acute hepatotoxicity we previously identified a pivotal role for mitochondrial SH3BP5 (SAB) as a target of JNK which sustains its activation through promotion of reactive oxygen species (ROS) production.
    AIM: Assess the role of hepatic SAB in experimental NASH and metabolic syndrome.
    RESULTS: In mice fed high-fat, high-calorie, high-fructose (HFHC) diet, SAB expression progressively increased through a sustained JNK/ATF2 activation loop. Inducible deletion of hepatic SAB markedly decreased sustained JNK activation and improved systemic energy expenditure at 8 weeks followed by decreased body fat at 16 weeks of HFHC diet. After 30 weeks mice treated with control-ASO developed steatohepatitis and fibrosis which was prevented by Sab-ASO treatment. P-JNK and P-ATF2 were markedly attenuated by Sab-ASO treatment. After 52 weeks of HFHC feeding control N-acetylgalactosamine antisense oligonucleotide (GalNAc-Ctl-ASO) treated mice fed the HFHC diet exhibited progression of steatohepatitis and fibrosis but GalNAc-Sab-ASO treatment from weeks 40 to 52 reversed these findings while decreasing hepatic SAB, P-ATF2, and P-JNK to chow fed levels.
    CONCLUSIONS: Hepatic SAB expression increases in HFHC diet fed mice. Deletion or knockdown of SAB inhibited sustained JNK activation and steatohepatitis, fibrosis, and systemic metabolic effects, suggesting that induction of hepatocyte Sab is an important driver of the interplay between the liver and the systemic metabolic consequences of overfeeding. In established NASH, hepatocyte targeted GalNAc-Sab-ASO treatment reversed steatohepatitis and fibrosis.
    Keywords:  NASH; antisense oligonucleotide (ASO); c-Jun-N-terminal kinase (JNK); fibrosis; insulin resistance
    DOI:  https://doi.org/10.1002/hep.32083
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