Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis

Diehl, Anna Mae; Day, Christopher P.

doi:10.1056/nejmra1503519

Cited by 1,031 publications

(974 citation statements)

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“…Characterized by hepatocyte damage, severe inflammation, and fibrosis, NASH is a complex process that results from multiple injury and repair responses triggered by lipotoxicity . Hepatocytes are the chief lipid‐handling cells and function as one of the earliest responders in response to lipotoxicity .…”

mentioning

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

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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.

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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

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“…Currently, the treatment of NAFLD is divided into three main categories: one is lifestyle changes, such as dietary adjustments, and increased physical activity; the second is control by clinical drugs; and the third is surgical intervention [3,12,34]. For the patient as a whole, changes in diet, energy intake control and increased exercise are still the first-line choice.…”

Section: Discussionmentioning

confidence: 99%

Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

Cheng

Chen

Jian

et al. 2018

Cell Physiol Biochem

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Background/Aims: Nonalcoholic steatohepatitis (NASH) is defined as lipid accumulation with hepatic injury, inflammation and early to moderate fibrosis. Kupffer cells play a crucial role in promoting hepatic inflammation, which further facilitates the development of NASH. Here we investigated the effects of Cangju Qinggan Jiangzhi decoction (CQJD) on high fat diet (HFD) and methionine-choline deficient (MCD) induced mouse NASH pathogenesis. Methods: Mouse NASH models were developed by HFD and MCD diet. The treated mice were divided into three groups: the control group (n = 10), the low-dose CQJD treatment group (n = 10) and the high-dose CQJD treatment group (n = 10). The hepatic injury, inflammation, and apoptotic molecules were evaluated by H&E staining, immunohistochemistry and real-time PCR. Kupffer cells were isolated from control mice and CQJD-treated mice after stimulation by lipopolysaccharide (LPS) and/or palmitic acid. The level of the inflammatory cytokines TNFα, IL1β, and CCL2 was measured by ELISA. Results: The HFD-fed mice displayed significant metabolic, inflammatory, and oxidative stress-related alterations due to hepatic lipid accumulation. CQJD treatment largely normalized the hepatic injury, lowered the ALT/AST level, and reduced the severity of liver inflammation, as revealed by the decreased inflammatory cytokines levels. In vitro, CQJD blocked the activation of LPS- or palmitic acid-primed Kupffer cells in a dose-dependent manner. In the MCD diet-induced NASH mice, similar therapeutic effects of CQJD were also observed. Conclusion: CQJD ameliorates mouse nonalcoholic steatohepatitis. The reduction in liver injury and inflammation induced by CQJD is associated with reduced activation of Kupffer cells. Our results suggest that CQJD is a promising therapeutic strategy in clinical steatohepatitis.

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“…Quantify the degree of severity of fatty infiltration in the liver allows a magnetic resonance imaging with contrast. Elastography (Fibroscan), which determines the density and presence of liver fibrosis with the help of elastic waves, is not informative at BMI greater than 30, that is, in obesity, and does not allow to differentiate steatosis from steatohepatitis [5].…”

Section: Introductionmentioning

confidence: 99%

The Influence of Environmental Factors on Nonalcoholic Fatty Liver Disease and Obesity

Kvit¹

2018

Development Trends in Medical Science and Practice: The Experience of Countries of Eastern Europe and Prospects of Ukraine

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Abstract. Non-alcoholic fatty liver disease (NAFLD) is the most common kind of liver injury in the world and its prevalence is due to the lack of "in-time" diagnosis and, as a consequence, treatment. A lot of different diseases are complicated by the fatty liver infiltration, the most often is obesity. The progress of the disease could depend on the environmental factors and the genetic disabilities. The aim of the review article was to analyze the latest data about the factors which impact on the NAFLD development in obese patients, including the gut microbiota, genetic predictors and environmental components, to find the new ways of pathogenesis, diagnosis and treatment. Non-alcoholic liver steatosis is diagnosed in 70% of obese patients (although some authors report a significantly higher (up to 95%) incidence of cases) and 35% of thin patients, and non-alcoholic steatohepatitis (NASH) -in 18.5% of obese patients and 2.7% -with insufficient body weight. Among patients with severe obesity and BMI more than 35 kg/m2, the prevalence of NAFLD and NASH is 91% and 37%, respectively. The combination of facts, available at the moment, suggests that one of the central role in the NAFLD development plays disturbance of intestinal microbiota and its permeability. Intestinal microflora can affect the NAFLD due to three mechanisms: 1) an increase in ethanol production in the intestinal cavity; 2) metabolic disorders of food choline (necessary for the synthesis of very low-density lipoproteins and elimination of liver lipids); 3) the release of bacterial lipopolysaccharides. The diagnostic methods, which allow investigation of fatty liver infiltration in the early stages, are considered. Despite the lower sensitivity and specificity compared with CT, ultrasound is considered as an acceptable first-line procedure for diagnostic NAFLD in clinical practice. The waist cir-

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Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis

Cited by 1,031 publications

References 58 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

Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

The Influence of Environmental Factors on Nonalcoholic Fatty Liver Disease and Obesity

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