Research Article Details
| Article ID: | A24345 |
| PMID: | 22981383 |
| Source: | Biochem Pharmacol |
| Title: | Endogenously synthesized n-3 polyunsaturated fatty acids in fat-1 mice ameliorate high-fat diet-induced non-alcoholic fatty liver disease. |
| Abstract: | Dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) have well-documented protective effects against obesity-induced insulin resistance and hepatic steatosis. Here, we investigated the effects of endogenous n-3 PUFAs on diet-induced fatty liver disease using fat-1 transgenic mice (fat-1) capable of converting n-6 to n-3 PUFAs. Wild-type (WT) and fat-1 mice were maintained on a high-fat diet (HFD) for 5months. HFD-induced weight gain and fatty liver were more prominent in WT mice than fat-1 mice. Histological analysis indicated that WT mice fed the HFD developed moderate-to-severe macrovesicular steatosis, whereas fat-1 mice developed very mild steatosis. In addition, HFD-induced hepatocyte ballooning and fibrosis were ameliorated in fat-1 mice. Serum alanine transaminase (ALT) and aspartate transaminase (AST) levels were within the respective normal ranges in HFD-fed fat-1 mice, whereas both were significantly elevated in HFD-fed WT mice. The fat-1 mice showed significantly decreased serum lipid levels, including triglycerides, total cholesterol (TC), HDL-C, and LDL-C, compared to WT mice regardless of diet. Specifically, the increases in very low-density lipoprotein cholesterol (VLDL-C) and chylomicrons detected in HFD-fed WT mice were completely blunted in HFD-fed fat-1 mice. Gene expression analysis showed that hepatic Cyp7a1 mRNA and protein expression levels were markedly increased in HFD-fed fat-1 mice. In addition, genes involved in cholesterol uptake (Ldlr) and bile acid excretion (Abcg5 and Abcg8) were increased in the livers of fat-1 mice. These data suggest that n-3 PUFAs ameliorate diet-induced hyperlipidemia and fatty liver through induction of CYP7A1 expression and activation of cholesterol catabolism to bile acid. |
| DOI: | 10.1016/j.bcp.2012.08.029 |
| 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 |
| 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 |
| 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 | |
|---|---|---|---|---|---|---|---|
| D258 | Omega 3 PUFA | Chemical drug | DB11133 | PPARG ligand; PPARA activator | Hypolipidemic drug | Under clinical trials | Details |
| D199 | L-alanine | Chemical drug | DB00160 | KYNU | -- | Failed in clinical trials | Details |
| 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 |
| D504 | Polyunsaturated Fatty Acids | Supplement | -- | -- | -- | Under clinical trials | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | Under clinical trials | Details |
| D125 | Epanova | Chemical drug | DB11133 | PPARG ligand; PPARA activator | Enhance lipid metabolism | Under clinical trials | Details |