Determinants of fibrosis progression and regression in NASH

Schuppan, Detlef; Surabattula, Rambabu; Wang, Xiaoyu

doi:10.1016/j.jhep.2017.11.012

Cited by 384 publications

(372 citation statements)

References 105 publications

Supporting

Mentioning

341

Contrasting

Unclassified

Order By: Relevance

“…Persistent inflammation has been suggested to promote HSC activation and LF . We therefore explored the effect of ASK1‐mediated hepatocyte inflammation on HSC activation.…”

Section: Resultsmentioning

confidence: 99%

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

Wang

Wen

et al. 2019

Hepatology

View full text Add to dashboard Cite

Activation of apoptosis signal‐regulating kinase 1 (ASK1) is a key driving force of the progression of nonalcoholic steatohepatitis (NASH) and represents an attractive therapeutic target for NASH treatment. However, the molecular and cellular mechanisms underlying ASK1 activation in the pathogenesis of NASH remain incompletely understood. In this study, our data unequivocally indicated that hyperactivated ASK1 in hepatocytes is a potent inducer of hepatic stellate cell (HSC) activation by promoting the production of hepatocyte‐derived factors. Our previous serial studies have shown that the ubiquitination system plays a key role in regulating ASK1 activity during NASH progression. Here, we further demonstrated that tumor necrosis factor receptor–associated factor 6 (TRAF6) promotes lysine 6 (Lys6)‐linked polyubiquitination and subsequent activation of ASK1 to trigger the release of robust proinflammatory and profibrotic factors in hepatocytes, which, in turn, drive HSC activation and hepatic fibrosis. Consistent with the in vitro findings, diet‐induced liver inflammation and fibrosis were substantially attenuated in Traf6+/– mice, whereas hepatic TRAF6 overexpression exacerbated these abnormalities. Mechanistically, Lys6‐linked ubiquitination of ASK1 by TRAF6 facilitates the dissociation of thioredoxin from ASK1 and N‐terminal dimerization of ASK1, resulting in the boosted activation of ASK1‐c‐Jun N‐terminal kinase 1/2 (JNK1/2)‐mitogen‐activated protein kinase 14(p38) signaling cascade in hepatocytes. Conclusion: These results suggest that Lys6‐linked polyubiquitination of ASK1 by TRAF6 represents a mechanism underlying ASK1 activation in hepatocytes and a key driving force of proinflammatory and profibrogenic responses in NASH. Thus, inhibiting Lys6‐linked polyubiquitination of ASK1 may serve as a potential therapeutic target for NASH treatment.

show abstract

“…Persistent inflammation has been suggested to promote HSC activation and LF . We therefore explored the effect of ASK1‐mediated hepatocyte inflammation on HSC activation.…”

Section: Resultsmentioning

confidence: 99%

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

Wang

Wen

et al. 2019

Hepatology

View full text Add to dashboard Cite

show abstract

“…In patients with NAFLD progression, excessive free fatty acid accumulation within hepatocytes leads to mitochondrial and peroxisomal dysfunction, leading to enhanced oxidative stress, production of toxic lipid metabolites, and ongoing hepatocyte injury through activation of nuclear factor kappa B and proinflammatory cytokines . Ongoing hepatocyte injury induced by endoplasmic reticulum stress, apoptosis, and chronic inflammation leads to liver fibrosis mediated by hepatic stellate cell activation and portal myofibroblasts, resulting in extracellular matrix deposition . More specifically, increased production and release of profibrogenic Hedgehog ligands by HBV‐infected hepatocytes and ballooned hepatocytes in NASH may lead to disease progression and hepatocarcinogenesis .…”

Section: Discussionmentioning

confidence: 99%

Nonalcoholic Steatohepatitis Is Associated With Liver‐Related Outcomes and All‐Cause Mortality in Chronic Hepatitis B

et al. 2019

View full text Add to dashboard Cite

Background and Aims Chronic hepatitis B (CHB) and nonalcoholic fatty liver disease are increasingly observed together in clinical practice, and development of nonalcoholic steatohepatitis (NASH) represents another leading cause of liver‐related morbidity and mortality. Our aims were to determine whether biopsy‐proven NASH impacts clinical outcomes in CHB patients and assess prognostic risk factors. Approach and Results CHB patients attending two tertiary centers in North America and Europe over 13 years with available clinical and biopsy data were included. Patients were categorized as no‐NASH or probable/definite NASH based on standardized histological assessment. Clinical events (death, decompensation, transplant, and hepatoma) were evaluated, and Kaplan‐Meier survival estimates and Cox proportional hazards regression were used to analyze the incidence of events. There were 1,089 CHB patients, classified as no‐NASH (n = 904, 83%) or NASH (n = 185, 17%), with 52 (6%) versus 27 (15%) experiencing outcome events during follow‐up, respectively. In the multivariable analysis adjusting for age, sex, hepatitis B e antigen serostatus, and diabetes, the presence of NASH and concomitant advanced fibrosis (AF) was significantly associated with clinical outcomes (hazard ratio [95% confidence interval], 4.8 [2.6‐9.0], P < 0.01) when compared to absence of NASH and AF (reference). NASH and AF were associated with a greater risk of outcomes compared to AF (P = 0.01) or NASH alone (P < 0.01). Of the three histological determinants of NASH, ballooning and inflammation, but not steatosis, were independently associated with clinical outcomes (P < 0.05) in place of NASH. NASH was significantly associated with increased risk of hepatocellular carcinoma and death (P < 0.01) but not decompensation (P = 0.33). Conclusions In our large combined tertiary center cohort, patients with concomitant NASH and CHB had more AF and shorter time to development of liver‐related outcomes or death compared to patients with CHB alone. Among patients with AF, superimposed NASH predicted poorer clinical outcomes.

show abstract

“…The mechanisms of regression of fibrosis in NASH are being investigated . A model for reversal would include not only loss of the initial fibrogenic stimuli (i.e., lipotoxicity and subsequent downstream effects) but also activation of fibrolytic, matrix degradation pathways in the genetically responsive host.…”

Section: Discussionmentioning

confidence: 99%

Improvements in Histologic Features and Diagnosis Associated With Improvement in Fibrosis in Nonalcoholic Steatohepatitis: Results From the Nonalcoholic Steatohepatitis Clinical Research Network Treatment Trials

Kleiner²,

et al. 2019

View full text Add to dashboard Cite

Hepatocellular injury and inflammation are believed to be the primary drivers of fibrogenesis that ultimately lead to cirrhosis in patients with nonalcoholic steatohepatitis (NASH). This study sought associations between observed improvements in fibrosis with improvement in specific histologic features, nonalcoholic fatty liver disease activity score (NAS) ≥2, diagnostic category, and primary histologically based outcomes of two adult NASH treatment trials. The primary outcome for the study was fibrosis improvement from baseline to end of treatment, defined as a 1‐point or more improvement in fibrosis stage. This is a retrospective analysis of biopsy data collected from the NASH Clinical Research Network Pathology Committee of Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH Trial (PIVENS) and Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial (FLINT) baseline and final biopsies. Treatment group–adjusted univariable and multivariable logistic regression models related improvement in fibrosis to improvements in other histologic variables, resolution of steatohepatitis, and improvement in the NAS ≥2. In PIVENS 221 subjects had baseline and 96‐week biopsies, and in FLINT 200 subjects had baseline and 72‐week biopsies. Improvement in fibrosis was found in 38% of PIVENS and 29% of FLINT biopsies; fibrosis improvement was more likely in treated than placebo subjects in both studies. Controlling for treatment group, fibrosis improvement was associated most strongly with resolution of NASH (PIVENS, odds ratio [OR], 3.9; 95% confidence interval [CI] 2.0‐7.6; P < 0.001; FLINT, OR, 8.0; 95% CI 3.1‐20.9; P < 0.001), and improved NAS by ≥2 (PIVENS, OR, 2.4; 95% CI 1.3‐4.3; P = 0.003; FLINT, OR, 4.2; 95% CI 2.1‐8.3; P < 0.001). Improvement in histologic features associated with improved fibrosis for both studies included steatosis, ballooning, Mallory‐Denk bodies, and portal, but not lobular, inflammation. Conclusion: These findings support a strong link between histologic resolution of steatohepatitis with improvement in fibrosis in NASH.

show abstract

Determinants of fibrosis progression and regression in NASH

Cited by 384 publications

References 105 publications

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

Nonalcoholic Steatohepatitis Is Associated With Liver‐Related Outcomes and All‐Cause Mortality in Chronic Hepatitis B

Improvements in Histologic Features and Diagnosis Associated With Improvement in Fibrosis in Nonalcoholic Steatohepatitis: Results From the Nonalcoholic Steatohepatitis Clinical Research Network Treatment Trials

Contact Info

Product

Resources

About