RGD Reference Report - Involvement of insulin resistance in the protective effect of metformin against alcoholic liver injury. - Rat Genome Database

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Involvement of insulin resistance in the protective effect of metformin against alcoholic liver injury.

Authors: Zhu, ZhanTao  Jiang, ZhiAn  Zhou, JunYing  Zhou, DongFang  Wang, Wei  Zhao, CaiYan  Zhen, Zhen  Nanji, Amin A 
Citation: Zhu Z, etal., Alcohol Clin Exp Res. 2014 Jun;38(6):1510-9. doi: 10.1111/acer.12418. Epub 2014 May 5.
RGD ID: 25824940
Pubmed: PMID:24797033   (View Abstract at PubMed)
DOI: DOI:10.1111/acer.12418   (Journal Full-text)


BACKGROUND: Alcoholic liver disease (ALD) continues to be a major cause of morbidity worldwide. The exact mechanisms for ALD pathogenesis are not fully understood. There is currently no known available drug for ALD. Previous studies have suggested that ethanol (EtOH)-induced hepatic insulin resistance, through the inhibition of adenosine monophosphate-activated protein kinase (AMPK) and the expression of adiponectin as well as downstream enzymes, contribute to the development of ALD. This study was to determine the effects of EtOH on AMPK activity as well as the protective effect of metformin.
METHODS: Forty male Wistar rats weighing 200 ± 20 g were randomized into 4 groups (n = 10) as follows: A = control group-rats received rodent chow; B = control + metformin group-rats received metformin (200 mg/kg/d intragastrically [IG]) at 21:00; C = EtOH group-rats were gavaged with alcohol of gradually increasing concentrations (30 to 60%, 5 to 9 g/kg/d) twice a day (9:00 and 16:00); D = EtOH + metformin group-rats received the same amount of EtOH as the rats in group C, and in addition received metformin (200 mg/kg/d IG) at 21:00. After 16 weeks, blood and liver samples were collected for further study.
RESULTS: Chronic EtOH consumption led to liver injury both histologically and biochemically accompanied by insulin resistance, reduced AMPK activity, and dysregulation of downstream enzymes. Decreased levels of circulating adiponectin and decreased expression of proliferator-activated receptor gamma coactivator-1α (PGC-1α) and peroxisome proliferator-activated receptors-α (PPAR-α) in the hepatic tissue were observed. Treatment with metformin attenuated the severity of liver injury, restored AMPK activity and normalized the expression of acetyl-CoA carboxylase and fatty acid synthase. In addition, metformin also increased the circulating adiponectin and liver adiponectin receptor 2 expression. Furthermore, PGC-1α and PPAR-α activities were also restored.
CONCLUSIONS: EtOH exposure induces hepatic insulin resistance. Metformin improved insulin resistance and reversed liver injury through the activation of AMPK and normalized adiponectin signaling making metformin a promising drug for the treatment of ALD.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ADIPOR2HumanAlcoholic Liver Diseases treatmentISOAdipor2 (Rattus norvegicus) RGD 
AI115388MouseAlcoholic Liver Diseases treatmentISOAdipor2 (Rattus norvegicus) RGD 
Adipor2RatAlcoholic Liver Diseases treatmentIEP  RGD 
ADIPOR2HumanInsulin Resistance treatmentISOAdipor2 (Rattus norvegicus) RGD 
AI115388MouseInsulin Resistance treatmentISOAdipor2 (Rattus norvegicus) RGD 
Adipor2RatInsulin Resistance treatmentIEP  RGD 

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ADIPOR2Humanethanol decreases expression ISOAdipor2 (Rattus norvegicus)ethanol decreases expression of Adipor2 mRNA in liverRGD 
AI115388Mouseethanol decreases expression ISOAdipor2 (Rattus norvegicus)ethanol decreases expression of Adipor2 mRNA in liverRGD 
Adipor2Ratethanol decreases expression EXP ethanol decreases expression of Adipor2 mRNA in liverRGD 
ADIPOR2Humanmetformin increases expression ISOAdipor2 (Rattus norvegicus)metformin increases expression of Adipor2 mRNA in liverRGD 
AI115388Mousemetformin increases expression ISOAdipor2 (Rattus norvegicus)metformin increases expression of Adipor2 mRNA in liverRGD 
Adipor2Ratmetformin increases expression EXP metformin increases expression of Adipor2 mRNA in liverRGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ADIPOR2Humanadiponectin signaling pathway  ISOAdipor2 (Rattus norvegicus) RGD 
AI115388Mouseadiponectin signaling pathway  ISOAdipor2 (Rattus norvegicus) RGD 
Adipor2Ratadiponectin signaling pathway  IEP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Adipor2  (adiponectin receptor 2)

Genes (Mus musculus)
AI115388  (EST AI115388)

Genes (Homo sapiens)
ADIPOR2  (adiponectin receptor 2)


Additional Information