MST1 Regulates Hepatocellular Lipophagy in Nonalcoholic Fatty Liver Disease

2021 ◽  
Author(s):  
Wang Li ◽  
Li Jia ◽  
Yuhan Li ◽  
Jianning Li ◽  
Hui Song ◽  
...  
Keyword(s):  
Liver Disease ◽  
Mouse Model ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Function Analysis ◽  
Protein Markers ◽  
Loss Of Function ◽  
Alcoholic Fatty Liver ◽  
The Impact

Abstract Background and Aims: Mammalia sterile 20-like kinase 1 (MST1) has recently been identified as an important regulator for the development of non-alcoholic fatty liver disease (NAFLD). However, the molecular mechanism of MST1 functions remains elusive. The current study is aiming to elucidate the impact and potential mechanism of MST1 in the disease progression of NAFLD. MethodsThe correlation of MST1 expression with NAFLD was determined in liver biopsy samples obtained from NAFLD patients by western blotting and IHC. The gain and loss of function analysis of MST1 was evaluated by the utilization of adenovirus or lentivirus mediated gene transfer. The impact of MST1 in lipophagy was examined by tracking the target protein markers through confocal microscopy and electron microscopy. Interaction of MST1 with the signaling molecule AMPKα/mTOR/ULK1 was evaluated by immune-blotting, in vitro kinase analysis and phosphorylation assays.Results: MST1 expression was inversely correlated with the hepatocellular lipid accumulation in both NAFLD patients and a mouse model. Impaired lipophagy was observed in the liver of Mst1-/- mice on a high fat diet. Restoration of MST1 promoted lipophagy and lipolysis in hepatocytes and the NAFLD mouse model. Further mechanistic approaches revealed that MST1 functioned to re-establish the dysfunctional autophagy/lipophagy pathway through targeting the AMPKα/mTOR/ULK1 interplay network. MST1 directly or indirectly activated ULK1 through coordination of AMPKα and mTOR/Raptor signaling pathways. Conclusions: MST1 may modulate hepatic lipid metabolism through restoration of dysfunctional autophagy and lipophagy, and thus might serve as an important therapeutic target for NAFLD.

The impact of a dedicated metabolic hepatology clinic for the treatment of non-alcoholic fatty liver disease

2017 ◽  
Author(s):  
Kenzo Motohashi ◽  
Ahmad Moolla ◽  
Tom Marjot ◽  
Mark Ainsworth ◽  
Jeremy Tomlinson ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
The Impact ◽  
Alcoholic Fatty Liver Disease

scholarly journals Two Metabolomics Phenotypes of Human Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease According to Fibrosis Severity

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 54
Author(s):  
Benjamin Buchard ◽  
Camille Teilhet ◽  
Natali Abeywickrama Samarakoon ◽  
Sylvie Massoulier ◽  
Juliette Joubert-Zakeyh ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Monounsaturated Fatty Acids ◽  
Metabolic Reprogramming ◽  
Resonance Spectroscopy ◽  
Alcoholic Fatty Liver ◽  
The Impact ◽  
Alcoholic Fatty Liver Disease

Non-Alcoholic Fatty Liver Disease (NAFLD) is considered as the forthcoming predominant cause for hepatocellular carcinoma (HCC). NAFLD-HCC may rise in non-cirrhotic livers in 40 to 50% of patients. The aim of this study was to identify different metabolic pathways of HCC according to fibrosis level (F0F1 vs. F3F4). A non-targeted metabolomics strategy was applied. We analyzed 52 pairs of human HCC and adjacent non-tumoral tissues which included 26 HCC developed in severe fibrosis or cirrhosis (F3F4) and 26 in no or mild fibrosis (F0F1). Tissue extracts were analyzed using 1H-Nuclear Magnetic Resonance spectroscopy. An optimization evolutionary method based on genetic algorithm was used to identify discriminant metabolites. We identified 34 metabolites differentiating the two groups of NAFLD-HCC according to fibrosis level, allowing us to propose two metabolomics phenotypes of NAFLD-HCC. We showed that HCC-F0F1 mainly overexpressed choline derivatives and glutamine, whereas HCC-F3F4 were characterized by a decreased content of monounsaturated fatty acids (FA), an increase of saturated FA and an accumulation of branched amino acids. Comparing HCC-F0F1 and HCC-F3F4, differential expression levels of glucose, choline derivatives and phosphoethanolamine, monounsaturated FA, triacylglycerides were identified as specific signatures. Our metabolomics analysis of HCC tissues revealed for the first time two phenotypes of HCC developed in NAFLD according to fibrosis level. This study highlighted the impact of the underlying liver disease on metabolic reprogramming of the tumor.

scholarly journals RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321767
Author(s):  
Marta B Afonso ◽  
Pedro M Rodrigues ◽  
Miguel Mateus-Pinheiro ◽  
André L Simão ◽  
Maria M Gaspar ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Body Weight Gain ◽  
Control Diet ◽  
Peroxisome Proliferator ◽  
Functional Link ◽  
Alcoholic Fatty Liver ◽  
The Impact ◽  
Alcoholic Fatty Liver Disease

ObjectiveReceptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD.DesignRIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3−/−) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks.ResultsRIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3−/− mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3−/− mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor γ (PPARγ) was increased in Ripk3−/− mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ in controlling fat deposition and fibrosis.ConclusionHepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.

scholarly journals The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease

Cell Cycle ◽  
2012 ◽  
Vol 11 (10) ◽  
pp. 1918-1928 ◽  
Author(s):  
Erin K. Daugherity ◽  
Gabriel Balmus ◽  
Ahmed Al Saei ◽  
Elizabeth S. Moore ◽  
Delbert Abi Abdallah ◽  
...  
Keyword(s):  
Dna Damage ◽  
Liver Disease ◽  
Mouse Model ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Dna Damage Checkpoint ◽  
Alcoholic Fatty Liver ◽  
Checkpoint Protein ◽  
Hepatocellular Apoptosis ◽  
Alcoholic Fatty Liver Disease

scholarly journals Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease

2014 ◽  
Vol 279 (3) ◽  
pp. 380-390 ◽  
Author(s):  
Banrida Wahlang ◽  
Ming Song ◽  
Juliane I. Beier ◽  
K. Cameron Falkner ◽  
Laila Al-Eryani ◽  
...  
Keyword(s):  
Liver Disease ◽  
Mouse Model ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Diet Induced Obesity ◽  
Alcoholic Fatty Liver Disease

scholarly journals Age, abdominal obesity, and glycated hemoglobin are associated with carotid atherosclerosis in type 2 diabetes patients with nonalcoholic fatty liver disease

2015 ◽  
Vol 17 (3) ◽  
pp. 300 ◽  
Author(s):  
Cristina Alina Silaghi ◽  
Horatiu Silaghi ◽  
Anca Elena Craciun ◽  
Anca Farcas ◽  
Horatiu Alexandru Colosi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Composition ◽  
Liver Disease ◽  
Fatty Liver ◽  
Abdominal Obesity ◽  
Fatty Liver Disease ◽  
Carotid Atherosclerosis ◽  
Alcoholic Fatty Liver ◽  
The Impact

Aim: The aim of this study was to evaluate the impact of clinical parameters and indices of body composition on the rela- tion between non-alcoholic fatty liver disease (NAFLD) and carotid intima-media thickness (cIMT), in a type 2 diabetes mel- litus population (T2DM). Material and methods: We retrospectively enrolled 336 T2DM outpatients who regularly attended Regina Maria Clinic in Cluj. Clinical, anthropometric and biochemical parameters were measured. Ultrasonography (US) was used to assess hepatic steatosis (HS) in all patients and cIMT in 146 subjects. Body composition was assessed by bioelectric impedance (BIA, InBody 720) in all patients. Results: cIMT was correlated with age (r=0.25; p=0.004), systolic blood pressure (r=0.18; p=0.041), glycated haemoglobin A1C (HbA1C, r=0.20; p=0.04), and with coronary artery disease (r=0.20; p=0.007). HS did not correlate with cIMT (r=0.04; p=0.64). cIMT was correlated with visceral fatty area (VFA, r=0.18; p=0.014) but not with other indices of body composition. Homeostasis model assessment for insulin resistance (HOMA-IR) was not correlated with cIMT (r=0.17; p=0.086). After multivariate analysis, age, HbA1c, and VFA were good independent predictors of cIMT (r=0.45; p˂0.001). Conclusions: These results are suggestive that in T2DM patients, fatty liver is not a direct mediator of early carotid atherosclerosis. Our data indicate that visceral fat accumulation and HbA1C are determinant factors of cIMT sugesting that controlling abdominal obesity and hyperglicemia might reduce atherosclerotic disease risk in NAFLD-T2DM subjects.

scholarly journals From NAFLD to MAFLD: Aligning Translational In Vitro Research to Clinical Insights

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 161
Author(s):  
Alexandra Gatzios ◽  
Matthias Rombaut ◽  
Karolien Buyl ◽  
Joery De Kock ◽  
Robim M. Rodrigues ◽  
...  
Keyword(s):  
Liver Disease ◽  
Drug Development ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Drug Testing ◽  
Disease Modeling ◽  
In Vitro Models ◽  
Alcoholic Fatty Liver ◽  
Short Term Exposure

Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver disease such as alcohol consumption or viral hepatitis do not need to be excluded. Revised nomenclature envisions speeding up and facilitating anti-MAFLD drug development by means of patient stratification whereby each subgroup would benefit from distinct pharmacological interventions. As human-based in vitro research fulfils an irrefutable step in drug development, action should be taken as well in this stadium of the translational path. Indeed, most established in vitro NAFLD models rely on short-term exposure to fatty acids and use lipid accumulation as a phenotypic benchmark. This general approach to a seemingly ambiguous disease such as NAFLD therefore no longer seems applicable. Human-based in vitro models that accurately reflect distinct disease subgroups of MAFLD should thus be adopted in early preclinical disease modeling and drug testing. In this review article, we outline considerations for setting up translational in vitro experiments in the MAFLD era and allude to potential strategies to implement MAFLD heterogeneity into an in vitro setting so as to better align early drug development with future clinical trial designs.

scholarly journals Activation of TAF9 via Danshensu-Induced Upregulation of HDAC1 Expression Alleviates Non-alcoholic Fatty Liver Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruiwen Wang ◽  
Zhecheng Wang ◽  
Ruimin Sun ◽  
Rong Fu ◽  
Yu Sun ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Protective Effect ◽  
Fatty Liver Disease ◽  
Cell Model ◽  
Signaling Mechanism ◽  
Alcoholic Fatty Liver

Fatty acid β-oxidation is an essential pathogenic mechanism in nonalcoholic fatty liver disease (NAFLD), and TATA-box binding protein associated factor 9 (TAF9) has been reported to be involved in the regulation of fatty acid β-oxidation. However, the function of TAF9 in NAFLD, as well as the mechanism by which TAF9 is regulated, remains unclear. In this study, we aimed to investigate the signaling mechanism underlying the involvement of TAF9 in NAFLD and the protective effect of the natural phenolic compound Danshensu (DSS) against NAFLD via the HDAC1/TAF9 pathway. An in vivo model of high-fat diet (HFD)-induced NAFLD and a palmitic acid (PA)-treated AML-12 cell model were developed. Pharmacological treatment with DSS significantly increased fatty acid β-oxidation and reduced lipid droplet (LD) accumulation in NAFLD. TAF9 overexpression had the same effects on these processes both in vivo and in vitro. Interestingly, the protective effect of DSS was markedly blocked by TAF9 knockdown. Mechanistically, TAF9 was shown to be deacetylated by HDAC1, which regulates the capacity of TAF9 to mediate fatty acid β-oxidation and LD accumulation during NAFLD. In conclusion, TAF9 is a key regulator in the treatment of NAFLD that acts by increasing fatty acid β-oxidation and reducing LD accumulation, and DSS confers protection against NAFLD through the HDAC1/TAF9 pathway.

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