Research Article Details
| Article ID: | A34199 |
| PMID: | 24145238 |
| Source: | Lab Invest |
| Title: | A novel mouse model of nonalcoholic steatohepatitis with significant insulin resistance. |
| Abstract: | Currently available models insufficiently reflect the pathogenic alternation of nonalcoholic steatohepatitis\NASH), such as insulin resistance. The present study aimed to characterize a novel NASH model caused by feeding the diet containing conjugated linoleic acid (CLA). In this study, mice were fed a control diet or the diet containing 0.5% CLA for 8 weeks. The insulin tolerance test (ITT) and homeostasis model assessment of insulin resistance (HOMA-IR) were used to determine the extent of insulin resistance. Liver lipotoxicity and inflammation were assessed by endoplasmic reticulum (ER) stress, autolipophagy, recruitment of Kupffer cells and hepatic stellate cell (HSC) activation. We found that liver weight was markedly increased, and histopathological examination showed marked macrosteatosis with focal hepatocellular death through apoptosis, and mild pericellular fibrosis with Kupffer cell recruitment and HSC activation, as well as light chain IIIβ-positive cells and enhanced ER stress in mice fed the CLA-containing diet. Enhanced synthesis and reduced β-oxidation of fatty acids resulted in their accumulation and lipotoxicity in hepatocytes. A biophotonic technology revealed lipid droplet accumulation in the liver from mice fed the CLA-containing diet, and Raman spectroscopic analysis indicated that these lipid droplets predominantly contained saturated fatty acids. Elevated fasting insulin levels, abnormal ITT and HOMA-IR confirmed the marked insulin resistance in these mice. Decreased phosphorylation of the insulin-signaling molecule Akt was partially responsible for the significant insulin resistance. In conclusion, Mice fed the diet containing CLA-developed steatohepatitis with marked insulin resistance, which is similar to the characteristics observed in NASH patients. The further characterization of this model would be particularly useful for revealing the critical role of insulin resistance in NASH development in conditions such as metabolic syndrome, diabetes and obesity. |
| DOI: | 10.1038/labinvest.2013.123 |
| 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 |
| 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 | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D083 | CLA | Chemical drug | DB01211 | KCNH2; SLCO1B1; SLCO1B3 | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |