Research Article Details
| Article ID: | A12108 |
| PMID: | 30599260 |
| Source: | Free Radic Biol Med |
| Title: | Loss of RIP3 initiates annihilation of high-fat diet initialized nonalcoholic hepatosteatosis: A mechanism involving Toll-like receptor 4 and oxidative stress. |
| Abstract: | Non-alcoholic fatty liver disease (NAFLD) is a prevalent and complex disease that confers a high risk of severe liver disorders. Although such public and clinical health importance, very few effective therapies are presently available for NAFLD. Here, we showed that receptor-interacting kinase-3 (RIP3) was up-regulated in liver of mouse with hepatic steatosis induced by high fat diet (HFD). After 16 weeks on a HFD, obesity, insulin resistance, metabolic syndrome, hepatic steatosis, inflammatory response and oxidative stress were significantly alleviated in liver of mice with the loss of RIP3. We provided mechanistic evidence that RIP3 knockdown attenuated hepatic dyslipidemia through preventing the expression of lipogenesis-associated genes. Furthermore, in the absence of RIP3, the transcription factor of nuclear factor-κB (NF-κB) signaling pathway activated by HFD was blocked, accompanied with the inhibition of NLRP3 inflammasome. We also found that RIP3 knockdown-induced activation of nuclear factor-erythroid 2 related factor 2/heme oxygenase-1 (Nrf-2/HO-1) led to the inhibition of oxidative stress. The detrimental effects of RIP3 on hepatic steatosis and related pathologies were confirmed in palmitate (PAL)-treated mouse liver cells. Of note, lipopolysaccharide (LPS)- or PAL-activated TLR-4 resulted in the up-regulation of RIP3 that was accompanied by the elevated inflammation and lipid deposition, and these effects were reversed in TLR-4 knockdown cells. Furthermore, promoting Nrf-2 pathway activation effectively reduced reactive oxygen species (ROS) generation and RIP3 expression in PAL-stimulated cells, consequently leading to the suppression of cellular inflammation and lipid accumulation. In contrast, blocking Nrf-2/HO-1 signaling abrogated RIP3 knockdown-reduced reactive oxygen species (ROS), inflammatory response and lipid deposition in PAL-stimulated cells. Taken together, the present study helped to elucidate how HFD-induced hepatic steatosis was regulated by RIP3, via the TLR-4/NF-κB and Nrf-2/HO-1 signaling pathways. |
| DOI: | 10.1016/j.freeradbiomed.2018.12.034 |
| 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 |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | 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 |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I13 | 3146 | Lipid metabolism disorder | An inherited metabolic disorder that involves the creation and degradation of lipids. http://en.wikipedia.org/wiki/Lipid_metabolism | disease of metabolism/ inherited metabolic disorder | Details |
| 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 | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D482 | Heme Oxygenase | Biological drug | -- | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |