Progress and challenges in the prevention and control of nonalcoholic fatty liver disease

Cai, Jingjing; Zhang, Xiaojing; Li, Hongliang

doi:10.1002/med.21515

Cited by 113 publications

(94 citation statements)

References 124 publications

(178 reference statements)

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“…(Hepatology 2020;71:93-111).T he global spike in metabolic disease and obesity has driven an epidemiological surge in nonalcoholic steatohepatitis (NASH). (1,2) As expected, NASH is rapidly emerging as one of the leading causes of liver transplantation and hepatocellular carcinoma (HCC) as well as one of the most common risk factor 94 of cardiovascular diseases (CVDs). (3,4) Given that there are no approved pharmacotherapies for NASH yet, it addresses an unmet need for identification of potential molecular targets for NASH therapy.Characterized by hepatocyte damage, severe inflammation, and fibrosis, (5) NASH is a complex process that results from multiple injury and repair responses triggered by lipotoxicity.…”

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confidence: 93%

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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: 93%

“…The global spike in metabolic disease and obesity has driven an epidemiological surge in nonalcoholic steatohepatitis (NASH) . As expected, NASH is rapidly emerging as one of the leading causes of liver transplantation and hepatocellular carcinoma (HCC) as well as one of the most common risk factor of cardiovascular diseases (CVDs) .…”

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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“…[101] However, this hypothesis was too simple and outdated. [103,104] In this section, the mechanisms are discussed on the view of inflammation, metabolic homeostasis, fibrosis and genetic factors related to NAFLD (Figure 2). [102] Our lab has made considerable achievements in identifying the pathogenesis of NAFLD and has revealed key molecular targets which could be potentially act as effective drug targets for NAFLD.…”

Section: Pathogenesismentioning

confidence: 99%

Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

et al. 2018

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Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease which affects ≈25% of the adult population worldwide, placing a tremendous burden on human health. The disease spectrum ranges from simple steatosis to steatohepatitis, fibrosis, and ultimately, cirrhosis and carcinoma, which are becoming leading reasons for liver transplantation. NAFLD is a complex multifactorial disease involving myriad genetic, metabolic, and environmental factors; it is closely associated with insulin resistance, metabolic syndrome, obesity, diabetes, and many other diseases. Over the past few decades, countless studies focusing on the investigation of noninvasive diagnosis, pathogenesis, and therapeutics have revealed different aspects of the mechanism and progression of NAFLD. However, effective pharmaceuticals are still in development. Here, the current epidemiology, diagnosis, animal models, pathogenesis, and treatment strategies for NAFLD are comprehensively reviewed, emphasizing the outstanding breakthroughs in the above fields and promising medications in and beyond phase II.

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“…NAFLD comprises a spectrum of histological abnormalities that occur in the liver, ranging from simple fatty liver (i.e., steatosis) to fatty liver coupled with inflammation, which is otherwise known as nonalcoholic steatohepatitis (NASH). NASH represents the advanced stage of the disease and is histologically characterized by steatosis, inflammation, hepatocyte ballooning, and fibrosis . Up to 20%‐30% of individuals with liver steatosis develop NASH, and more than 30% of patients who develop NASH may progress to cirrhosis or hepatocellular carcinoma (HCC) .…”

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The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis

2019

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Inflammation and metabolic dysfunction are hallmarks of nonalcoholic steatohepatitis (NASH), which is one of the fastest‐growing liver diseases worldwide. Emerging evidence indicates that innate immune mechanisms are pivotal drivers of inflammation and other pathological manifestations observed in NASH, such as hepatosteatosis, insulin resistance (IR), and fibrosis. This robust innate immune reaction is intrinsic to the liver, which is an important immunological organ that contains a coordinated network of innate immune cells, including Kupffer cells (KCs), dendritic cells (DCs), and lymphocytes. Hepatocytes and liver sinusoidal endothelial cells (LSECs) are not formally innate immune cells, but they take on immune cell function when stressed. These cells can sense excess metabolites and bacterial products and translate those signals into immune responses and pathological hepatic changes during the development of NASH. In this review, we take a historical perspective in describing decades of research that aimed to identify the key molecular and cellular players in the innate immune system in the setting of NASH. Furthermore, we summarize the innate immune cells that are involved in the progression of NASH and illustrate how they sense disturbances in circulating metabolic factors by innate immune receptors and subsequently initiate the intercellular signaling cascades that lead to persistent inflammation and progression of hepatic complications.

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Progress and challenges in the prevention and control of nonalcoholic fatty liver disease

Cited by 113 publications

References 124 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

Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis

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