Research Article Details
| Article ID: | A49175 |
| PMID: | 15489566 |
| Source: | Eur J Gastroenterol Hepatol |
| Title: | Mitochondrial injury in steatohepatitis. |
| Abstract: | Rich diet and lack of exercise are causing a surge in obesity, insulin resistance and steatosis, which can evolve into steatohepatitis. Patients with non-alcoholic steatohepatitis have increased lipid peroxidation, increased tumour necrosis factor-alpha (TNF-alpha) and increased mitochondrial beta-oxidation rates. Their in-vivo ability to re-synthesize ATP after a fructose challenge is decreased, and their hepatic mitochondria exhibit ultrastructural lesions, depletion of mitochondrial DNA and decreased activity of respiratory chain complexes. Although the mechanisms for these effects is unknown, the basal cellular formation of reactive oxygen species (ROS) may oxidize fat deposits to cause lipid peroxidation, which damages mitochondrial DNA, proteins and cardiolipin to partially hamper the flow of electrons within the respiratory chain. This flow may be further decreased by TNF-alpha, which can release cytochrome c from mitochondria. Concomitantly, the increased mitochondrial fatty acid beta-oxidation rate augments the delivery of electrons to the respiratory chain. Due to the imbalance between a high electron input and a restricted outflow, electrons may accumulate within complexes I and III, and react with oxygen to form the superoxide anion radical. Increased mitochondrial ROS formation could in turn directly oxidize mitochondrial DNA, proteins and lipids, enhance lipid peroxidation-related mitochondrial damage, trigger hepatic TNF-alpha formation and deplete antioxidants, thus further blocking electron flow and further increasing mitochondrial ROS formation. Mitochondrial dysfunction plays an important role in liver lesions, through the ROS-induced release of both biologically active lipid peroxidation products and cytokines. In particular, the up-regulation of both TNF-alpha and Fas triggers mitochondrial membrane permeability and apoptosis. The ingestion of apoptotic bodies by stellate cells stimulates fibrogenesis, which is further activated by lipid peroxidation products and high leptin levels. Chronic apoptosis is compensated by increased cell proliferation, which, together with oxidative DNA damage, may cause gene mutations and cancer. |
| DOI: | 10.1097/00042737-200411000-00003 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S08 | Lifestyle measures | Lifestyle intervention; weight loss; diet adaptation; dietary interventions; lifestyle modifications; Exercise | -- | -- | Details |
| 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 |
| 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 |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D142 | Fructose | Chemical drug | DB04173 | -- | Intravenous nutrition drug | Under clinical trials | Details |
| D018 | Aspirin | Chemical drug | DB00945 | AKR1C1 inhibitor; PCNA downregulator | Enhance lipid metabolism | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D094 | Cysteamine | Chemical drug | DB00847 | GSS stimulant | Renal drug | Under clinical trials | Details |
| D095 | Cysteamine bitartrate | Chemical drug | DB00847 | -- | -- | Under clinical trials | Details |