Research Article Details
| Article ID: | A16152 |
| PMID: | 28536120 |
| Source: | FASEB J |
| Title: | Hepatocyte-specific sirtuin 6 deletion predisposes to nonalcoholic steatohepatitis by up-regulation of Bach1, an Nrf2 repressor. |
| Abstract: | Sirtuin (Sirt)6 has been implicated in negative regulation of inflammation and lipid metabolism, although its function in the progression from simple steatosis to nonalcoholic steatohepatitis (NASH) remains to be defined. To explore the role of hepatocyte Sirt6 in NASH development, we generated hepatocyte-specific Sirt6-knockout (KO) mice that were fed a high-fat and high-fructose (HFHF) diet for 16 wk. HFHF-fed KO mice had increased hepatic steatosis and inflammation and aggravated glucose intolerance and insulin resistance compared with wild-type mice. HFHF-induced liver fibrosis and oxidative stress and related gene expression were significantly elevated in KO mice. In the livers of KO mice, nuclear factor erythroid 2-related factor 2 (Nrf2) was down-regulated; conversely, BTB domain and CNC homolog 1 (Bach1), a nuclear repressor of Nrf2, were up-regulated. We discovered that Sirt6, which interacts with Bach1 under basal condition, induces its detachment from the antioxidant response element (ARE) region of heme oxygenase 1 promoter. Furthermore, we found that Sirt6 promotes Nrf2 binding to ARE in response to oxidative stimuli, which leads to the expression of phase II/antioxidant enzymes. Finally, we showed that HFHF-induced steatosis, inflammation, and fibrosis were ameliorated by adenoviral Sirt6 overexpression. Sirt6 may be a useful therapeutic target for amelioration of NASH by curbing inflammation and oxidative stress.-Ka, S.-O, Bang, I. H., Bae, E. J., Park, B.-H. Hepatocyte-specific sirtuin 6 deletion predisposes to nonalcoholic steatohepatitis by up-regulation of Bach1, an Nrf2 repressor. |
| DOI: | 10.1096/fj.201700098RR |
| 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 |
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | 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 |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D545 | Pig placenta extract | Biological extract | -- | -- | -- | Under clinical trials | Details |
| D482 | Heme Oxygenase | Biological drug | -- | -- | -- | Under clinical trials | 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 |