Disease Information

General Information of the Disease (ID: DIS00316)
Name
Nonalcoholic fatty liver disease
ICD
ICD-11: DB92
Resistance Map
Type(s) of Resistant Mechanism of This Disease
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
4 drug(s) in total
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Doxepin
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Facilitated glucose transporter member 4 (GLUT4) [1]
Resistant Disease Nonalcoholic fatty liver disease [ICD-11: DB92.0]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Drug Doxepin
 Drug Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation AKT signaling pathway Inhibition hsa04151
In Vivo Model Male C57BL/6J mouse model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Intraperitoneal glucose tolerance test (IPGTT)
Mechanism Description Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice. Doxepin exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. Doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes.
Fenofibrate
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Protein phosphatase 3 catalytic subunit alpha (PPP3CA) [2]
Sensitive Disease Nonalcoholic fatty liver disease [ICD-11: DB92.0]
Molecule Alteration Function
Activation
 Molecule Info 
Sensitive Drug Fenofibrate
 Drug Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation Intracellular calcium flux signaling pathway Activation hsa05207
TFEB/TFE3 nuclear translocation Activation hsa04137
Cell autophagy Activation hsa04140
CaMKKbeta-AMPK signaling pathway Activation hsa04152
In Vivo Model HFD-fed mouse model Mus musculus
Mechanism Description Administration of fenofibrate effectively ameliorated glucose intolerance and insulin resistance in HFD-fed mice. In this study, fenofibrate treatment appeared to increase intracellular calcium flux and TFEB/TFE3 nuclear translocation and autophagy through two different mechanisms. One is the aforementioned calcium-mediated upregulation of the CaMKKbeta-AMPK pathway and the other is the activation of the calcium-dependent dephosphatase calcineurin subunit PPP3CA.
Idebenone
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: SHC-transforming protein 1 (SHC1) [3]
Resistant Disease Nonalcoholic fatty liver disease [ICD-11: DB92.0]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Drug Idebenone
 Drug Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vivo Model Fast food diet (FFD) mouse model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Glucose tolerance test (GTT); Insulin tolerance test (ITT)
Mechanism Description In the metabolic FFD model, idebenone administration improved insulin resistance, and reduced inflammation and fibrosis shown with qPCR, hydroxyproline measurement, and histology.
Sorafenib
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: TNF alpha induced protein 8 (TNFAIP8) [4]
Resistant Disease Hepatic Steatosis [ICD-11: DB92.Y]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Drug Sorafenib
 Drug Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/mTOR signaling pathway Inhibition hsa04150
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
SK-Hep1 cells Ascites Homo sapiens (Human) CVCL_0525
PLC/PRF/5 cells Liver Homo sapiens (Human) CVCL_0485
In Vivo Model C57BL/6J mice Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; RT/qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins.
Key Molecule: TNF alpha induced protein 8 (TNFAIP8) [4]
Resistant Disease Hepatic Steatosis [ICD-11: DB92.Y]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Drug Sorafenib
 Drug Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/mTOR signaling pathway Inhibition hsa04150
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
SK-Hep1 cells Ascites Homo sapiens (Human) CVCL_0525
PLC/PRF/5 cells Liver Homo sapiens (Human) CVCL_0485
In Vivo Model C57BL/6J mice Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; RT/qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins.
Key Molecule: TNF alpha induced protein 8 (TNFAIP8) [4]
Resistant Disease Hepatic Steatosis [ICD-11: DB92.Y]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Drug Sorafenib
 Drug Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/mTOR signaling pathway Inhibition hsa04150
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
SK-Hep1 cells Ascites Homo sapiens (Human) CVCL_0525
PLC/PRF/5 cells Liver Homo sapiens (Human) CVCL_0485
In Vivo Model C57BL/6J mice Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; RT/qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins.
Key Molecule: TNF alpha induced protein 8 (TNFAIP8) [4]
Resistant Disease Hepatic Steatosis [ICD-11: DB92.Y]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Drug Sorafenib
 Drug Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/mTOR signaling pathway Inhibition hsa04150
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
SK-Hep1 cells Ascites Homo sapiens (Human) CVCL_0525
PLC/PRF/5 cells Liver Homo sapiens (Human) CVCL_0485
In Vivo Model C57BL/6J mice Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; RT/qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins.
Investigative Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Nonesterified
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Maternally expressed 3 (MEG3) [5]
Resistant Disease Nonalcoholic fatty liver disease [ICD-11: DB92.0]
Molecule Alteration Down-regulation
Expression
 Molecule Info 
Resistant Drug Nonesterified
 Drug Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
In Vivo Model C57BL/6 mice model Mus musculus
Experiment for
Molecule Alteration		 Overexpression assay; Dual luciferase assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description LncRNA MEG3 functions as a ceRNA in regulating hepatic lipogenesis by competitively binding to miR-21 with LRP6.
Key Molecule: H19, imprinted maternally expressed transcript (H19) [6]
Resistant Disease Nonalcoholic fatty liver disease [ICD-11: DB92.0]
Molecule Alteration Up-regulation
Interaction
 Molecule Info 
Resistant Drug Nonesterified
 Drug Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
HepG2 cells Liver Homo sapiens (Human) CVCL_0027
In Vivo Model C57BL/6 mice model Mus musculus
Experiment for
Molecule Alteration		 IHC staining assay; ELISA assay; Luciferase assay; RNA pull down assay; qRT-PCR; Western bloting analysis; Overexpression assay; Knockdown assay
Mechanism Description LncRNA-H19 promotes hepatic lipogenesis by directly regulating miR-130a/PPAR gama axis in nonalcoholic fatty liver disease.
References
Ref 1 Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice .Pharmaceuticals (Basel). 2021 Mar 16;14(3):267. doi: 10.3390/ph14030267. 10.3390/ph14030267
Ref 2 Fenofibrate, a PPARAlpha agonist, reduces hepatic fat accumulation through the upregulation of TFEB-mediated lipophagy .Metabolism. 2021 Jul;120:154798. doi: 10.1016/j.metabol.2021.154798. Epub 2021 May 11. 10.1016/j.metabol.2021.154798
Ref 3 Shc inhibitor idebenone ameliorates liver injury and fibrosis in dietary NASH in mice .J Biochem Mol Toxicol. 2021 Oct;35(10):e22876. doi: 10.1002/jbt.22876. Epub 2021 Aug 8. 10.1002/jbt.22876
Ref 4 TNFAIP8 regulates autophagy, cell steatosis, and promotes hepatocellular carcinoma cell proliferation .Cell Death Dis. 2020 Mar 9;11(3):178. doi: 10.1038/s41419-020-2369-4. 10.1038/s41419-020-2369-4
Ref 5 LncRNA MEG3 contributes to adenosine-induced cytotoxicity in hepatoma HepG2 cells by downregulated ILF3 and autophagy inhibition via regulation PI3K-AKT-mTOR and beclin-1 signaling pathwayJ Cell Biochem. 2019 Oct;120(10):18172-18185. doi: 10.1002/jcb.29123. Epub 2019 May 29.
Ref 6 Downregulation of lncRNA H19 sensitizes melanoma cells to cisplatin by regulating the miR-18b/IGF1 axisAnticancer Drugs. 2020 Jun;31(5):473-482. doi: 10.1097/CAD.0000000000000888.

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