Research Article Details
| Article ID: | A25788 |
| PMID: | 21455726 |
| Source: | Diabetologia |
| Title: | Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease. |
| Abstract: | AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) is associated with insulin resistance and characterised by different degrees of hepatic lesion. Its pathogenesis and correlation with apoptosis and insulin resistance in insulin target tissues remains incompletely understood. We investigated how insulin signalling, caspase activation and apoptosis correlate with different NAFLD stages in liver, muscle and visceral adipose tissues. METHODS: Liver, muscle and adipose tissue biopsies from 26 morbidly obese patients undergoing bariatric surgery were grouped according to the Kleiner-Brunt scoring system into simple steatosis, and less severe and more severe non-alcoholic steatohepatitis (NASH). Apoptosis was assessed by DNA fragmentation, and caspase-2 and -3 activation. Insulin signalling and c-Jun NH(2)-terminal kinase (JNK) proteins were evaluated by western blot. RESULTS: Caspase-3 and -2 activation, and DNA fragmentation were markedly increased in the liver of patients with severe NASH vs in that of those with simple steatosis (p < 0.01). Muscle tissue, and to a lesser extent the liver, had decreased tyrosine phosphorylated insulin receptor and insulin receptor substrate in patients with severe NASH, compared with those with simple steatosis (p < 0.01 muscle; p < 0.05 liver). Concomitantly, Akt phosphorylation decreased in muscle, liver and visceral adipose tissues in patients with severe NASH (at least p < 0.05). Finally, JNK phosphorylation was significantly increased in muscle (p < 0.01) and liver (p < 0.05) from NASH patients, compared with tissue from those with simple steatosis. CONCLUSIONS/INTERPRETATION: Our results demonstrate a link between apoptosis, insulin resistance and different NAFLD stages, where JNK and caspase-2 may play a key regulatory role. |
| DOI: | 10.1007/s00125-011-2130-8 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S13 | Anti-apoptosis | hepatocyte apoptosis; hepatic autophagy; apoptosis | Pan-caspase inhibitor | Emricasan | Details |
| S09 | Bariatric surgery | Metabolic surgery | -- | -- | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T11 | Caspase-3 | CASP3 | inhibitor | Enzyme | P42574 | CASP3_HUMAN | Details |
| T37 | Caspase-2 | CASP2 | inhibitor | Enzyme | P42575 | CASP2_HUMAN | Details |
| T07 | Bile acid receptor | NR1H4 | agonist | Nuclear hormone receptor | Q96RI1 | NR1H4_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |