Research Article Details
| Article ID: | A25094 |
| PMID: | 22176347 |
| Source: | Hepatol Res |
| Title: | High fat diet induced hepatic steatosis and insulin resistance: Role of dysregulated ceramide metabolism. |
| Abstract: | AIM:   Non-alcoholic fatty liver disease (NAFLD) is an insulin resistance disease that can progress to cirrhosis and liver failure. We hypothesized that in NAFLD, insulin resistance dysregulates lipid metabolism, increasing production of cytotoxic lipids including ceramides, which exacerbate hepatic insulin resistance and injury. METHODS:   Long Evans rats were pair-fed low (LFD) or high (HFD) fat diets for 8 weeks. Livers were used to measure lipids, gene expression, insulin receptor binding, integrity of insulin signaling, and pro-inflammatory cytokines. In vitro experiments characterized effects of ceramides on Huh7 cell viability, mitochondrial function, and insulin signaling. RESULTS:   High fat diet feeding caused NAFLD with peripheral and hepatic insulin resistance, increased hepatic expression of pro-ceramide genes, sphingomyelinase activity, and lipid peroxidation, and increased serum ceramide. Ceramide treatment impaired Huh7 cell viability, mitochondrial function, and insulin signaling. CONCLUSIONS:   Increased hepatic ceramide generation and release may mediate both hepatic and peripheral insulin resistance in NAFLD. |
| DOI: | 10.1111/j.1872-034X.2011.00934.x |
| 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 |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name |
|---|
| 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 |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | 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 |