From NASH to HCC: current concepts and future challenges

Anstee, Quentin M.; Reeves, Helen L.; Kotsiliti, Eleni; Govaere, Olivier; Heikenwälder, Mathias

doi:10.1038/s41575-019-0145-7

Cited by 1,064 publications

(1,022 citation statements)

References 291 publications

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“…However, in this study, active STAT3 induced laminin and laminin 2 expression, presumably in hepatocytes, whereas collagen I in HSCs. A certain proportion of patients with NASH and fibrosis (from 2.4% to 12.8% with or without cirrhosis) will sequentially develop HCC (Anstee et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…The immune-metabolic aspects of nonalcoholic fatty liver disease (NAFLD) and NASH can be investigated as approaches to block the progression to HCC (Anstee et al, 2019;Sircana et al, 2019). Nonalcoholic injury-mediated liver inflammation causes production of diverse cytokines (Biancheri et al, 2014) and chemokines (Marra & Tacke, 2014), which may facilitate ECM production and subsequent fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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Differential TM4SF5-mediated SIRT1 modulation and signaling for chronic liver disease

Ryu

Kim

Kang

et al. 2020

Preprint

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Here we show the roles of transmembrane 4 L six family member 5 (TM4SF5) in the progression of nonalcoholic steatosis (or NAFL) to steatohepatitis (NASH). The overexpression of TM4SF5 caused nonalcoholic steatosis and NASH in an age-dependent manner. Initially, TM4SF5-positive hepatocytes and livers exhibited lipid accumulation, decreased SIRT1, increased SREBPs levels, and inactive STAT3 via SOCS1/3 upregulation. In older animals, TM4SF5 under an inflammatory environment increased SIRT1 expression and STAT3 activity with no significant change to SOCSs and SREBPs levels, leading to active STAT3-mediated fibrotic extracellular matrix (ECM) production. Liver tissues from clinical human patients with NAFL or NASH also showed such a TM4SF5-SIRT1-STAT3-ECM relationship correlated with fibrosis score and age. Ligand-independent and TM4SF5-mediated STAT3 activity led to collagen I and laminins/laminin γ2 expression in hepatic stellate cells and hepatocytes, respectively. Laminin γ2 suppression abolished CCl4-mediated liver damage and ECM production and reduced SIRT1 and active-STAT3, but did not alter SREBP1 or SOCSs levels. These findings suggest that TM4SF5, CCL20, SIRT1, and/or laminin γ2 may be promising therapeutic targets against liver disease. the Tumor Microenvironment GCRC (2011-0030001) to JWL. Author contributions JR and EK performed most experiments; EK and MKK helped animal experiments; JWJ, SHN, JEK, DGS, and HJK helped with imaging experiments and with reagents; JHL, JHY, and HYK helped with clinical patient tissues; TS helped with the RNA-Seq analysis; SK helped with anti-TM4SF5 antibodies; JWL designed the experiments and wrote the manuscript. Conflict of interestsThe authors declare no competing interests. 26The paper explained PROBLEM: Nonalcoholic liver disease is a chronic disease with immuno-metabolic disorders during NAFLD progression to NASH/fibrosis, cirrhosis and cancer. The molecular mechanisms for the earlier progression to NASH/fibrosis remain unclear. RESULTS:Tm4sf5-engineered mice revealed that TM4SF5-dependent SIRT1 modulation and chemokines promoted NAFLD, NASH, and fibrosis in an age-dependent manner.TM4SF5/STAT3-mediated laminin expression in hepatocytes critically promoted the earlier progression toward NASH.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential TM4SF5-mediated SIRT1 modulation and signaling for chronic liver disease

Ryu

Kim

Kang

et al. 2020

Preprint

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“…In the recent decades, the incidence of nonalcoholic fatty liver disease (NAFLD) increases rapidly and becomes a huge threat to public health of the whole world. Nonalcoholic steatohepatitis (NASH) is the aggressive subtype of NAFLD and is becoming the main cause for liver cirrhosis, hepatocellular carcinoma or liver transplantation in USA (1)(2)(3). Regarding the mechanisms involved in the pathogenesis of NASH, it is now widely recognized that hepatic lipid accumulation and increased free fatty acids (FFA) causes lipotoxicity to hepatocytes and induces cell death, which is accompanied by the massive recruitment of monocytes into liver and the occurrence of chronic inflammation (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

RIP1 kinase activity promotes steatohepatitis through mediating cell death and inflammation in macrophages

Tao

Chen

et al. 2020

Preprint

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Hepatocyte cell death and liver inflammation have been well recognized as central characteristics of nonalcoholic steatohepatitis (NASH), however, the underlying molecular basis remains elusive. The kinase receptor-interacting protein 1 (RIP1) is a key regulator of apoptosis, necroptosis and inflammation, we thus hypothesized that the kinase activity of RIP1 may be involved in the pathogenesis of NASH. Wild-type and RIP1 kinase-dead (Rip1 K45A/K45A ) mice were fed with methionine-and choline-deficient diet (MCD) or high-fat diet (HFD) to establish distinct NASH models. In both models, compared to WT mice, Rip1 K45A/K45A mice exhibited significantly less liver injury, less steatosis, decreased inflammation, and less cell death in liver tissue. Moreover, hepatic fibrosis as characterized by Sirius Red staining, expression of α-SMA and other fibrosis markers, were significantly alleviated in Rip1 K45A/K45A mice than WT controls. Furthermore, using bone marrow transplantation to create chimeric mice, we found that it is the RIP1 kinase in hematopoietic-derived macrophages contributing mostly to the disease progression in NASH.Results from in vitro studies were in agreement with the in vivo data, demonstrating that RIP1 kinase was required for inflammasome activation and cell death induced by saturated fatty acid (palmitic acid) in bone marrow-derived macrophages (BMDMs). At last, we also found that the phosphorylation and expression of RIP1 was obviously increased in patients with NAFLD or NASH, but not in healthy controls. In summary, our results indicate that RIP1 kinase is activated during the pathogenesis of steatohepatitis, and consequently induces inflammation and cell death in macrophages, contributing to the disease progression. Our study suggests that macrophage RIP1 kinase represents a specific and potential target for the treatment of NASH.

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“…Liver fibrosis results from the accumulation of collagen scar tissue following chronic liver injuries caused by nonalcoholic steatohepatitis (NASH), alcohol, hepatitis viral infection and autoimmune hepatitis 1, 2 . Chronic liver fibrosis progresses into hepatocellular carcinoma and cirrhosis with characteristics of ascites, jaundice (yellow skin), hepatic hypertension and hepatic encephalopathy if the cause is not eliminated 3 .…”

Section: Introductionmentioning

confidence: 99%

Hepatocytic Prominin-1 protects against liver fibrosis by stabilizing the SMAD7 protein

Lee¹,

Dong²,

Um³

et al. 2019

Preprint

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Background and Aims:Prominin-1 (PROM1) is known to be upregulated in hepatocytic progenitor cells (HPCs) and cholangiocytes of fibrotic livers. To understand the function of upregulated PROM1 during liver fibrosis, we analyzed liver fibrosis from global and liverspecific Prom1 knockout mice and investigated the molecular mechanism of how Prom1 protects the liver against liver fibrosis. Methods:We analyzed PROM1 expression from human liver with mild and severe liver fibrosis (n=4-9). Liver fibrosis was induced by carbon tetrachloride (CCl 4 ) treatment and bile duct ligation (BDL) from wild type and global and liver-specific knockout mice (n=3-13).The severity of liver fibrosis was determined by qRT-PCR, immunostaining and immunoblotting for fibrotic markers such as αSMA, collagen. TGFβ signaling was also analyzed from fibrotic liver and primary hepatocytes of wild type and global and liverspecific knockout mice (n=3-5). Molecular interaction between PROM1 and SMAD7 was determined by endogenous and exogenous co-immunoprecipitation.Results: PROM1 was found in the plasma membranes of both healthy and fibrotic hepatocytes and cholangiocytes. Global Prom1 knockout aggravated BDL-and CCl 4 -induced liver fibrosis. Prom1 -/hepatocytes showed increased TGFβ signaling due to reduced SMAD7 protein expression compared to that in wild-type hepatocytes. PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that liver-specific Prom 1 knockout aggravated BDL-induced liver fibrosis due to reduced levels of SMAD7. Conclusion:Hepatocytic PROM1 stabilizes SMAD7, preventing TGFβ signaling. Thus, PROM1 is necessary for the negative regulation of TGFβ signaling during liver fibrosis.

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From NASH to HCC: current concepts and future challenges

Cited by 1,064 publications

References 291 publications

Differential TM4SF5-mediated SIRT1 modulation and signaling for chronic liver disease

Differential TM4SF5-mediated SIRT1 modulation and signaling for chronic liver disease

RIP1 kinase activity promotes steatohepatitis through mediating cell death and inflammation in macrophages

Hepatocytic Prominin-1 protects against liver fibrosis by stabilizing the SMAD7 protein

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