Research Article Details
| Article ID: | A07756 |
| PMID: | 32363320 |
| Source: | Hepatol Commun |
| Title: | Validation of PAS Kinase, a Regulator of Hepatic Fatty Acid and Triglyceride Synthesis, as a Therapeutic Target for Nonalcoholic Steatohepatitis. |
| Abstract: | Hyperactivation of sterol regulatory element binding protein 1c (SREBP-1c), which transcriptionally induces expression of enzymes responsible for de novo lipogenesis and triglyceride (TG) formation, is implicated in nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) pathogenesis. Posttranslational SREBP-1c maturation and activation is stimulated by the protein per-arnt-sim kinase (PASK). PASK-knockout mice are phenotypically normal on a conventional diet but exhibit decreased hypertriglyceridemia, insulin resistance, and hepatic steatosis on a high-fat diet. We investigated the effects of pharmacologic PASK inhibition using BioE-1115, a selective and potent oral PASK inhibitor, in Zucker fatty (fa)/fa) rats, a genetic model of obesity, dyslipidemia, and insulin resistance, and in a dietary murine model of NAFLD/NASH. Female Zucker (fa/fa) rats and lean littermate (fa/+) controls received BioE-1115 (3-100 mg/kg/day) and/or omega-3 fatty acids, and blood glucose, hemoglobin A1c, glucose tolerance, insulin, and serum TG were measured. C57BL/6J mice fed a high-fat/high-fructose diet (HF-HFrD) were treated with BioE-1115 (100 mg/kg/day) or vehicle. Body weight and fasting glucose were measured regularly; serum TG, body and organ weights, and liver TG and histology were assessed at sacrifice. Messenger RNA (mRNA) abundance of SREBP-1c target genes was measured in both models. In Zucker rats, BioE-1115 treatment produced significant dose-dependent reductions in blood glucose, insulin, and TG (all greater than omega-3 fatty acids) and dose dependently restored insulin sensitivity assessed by glucose tolerance testing. In HF-HFrD mice, BioE-1115 reduced body weight, liver weight, fasting blood glucose, serum TGs, hepatic TG, hepatic fibrosis, hepatocyte vacuolization, and bile duct hyperplasia. BioE-1115 reduced SREBP-1c target mRNA transcripts in both models. Conclusion: PASK inhibition mitigates many adverse metabolic consequences associated with an HF-HFrD and reduces hepatic fat content and fibrosis. This suggests that inhibition of PASK is an attractive therapeutic strategy for NAFLD/NASH treatment. |
| DOI: | 10.1002/hep4.1498 |
| 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 |
| S07 | Anti-lipogenesis | de novo lipogenesis; de novo lipogenesis; DNL; anti-lipogenic mechanisms; adipogenesis; anti-obesity | stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor | Aramchol; Firsocostat (GS-0976); VK-2809; ION 224 | 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 | |
|---|---|---|---|---|---|---|---|
| D258 | Omega 3 PUFA | Chemical drug | DB11133 | PPARG ligand; PPARA activator | Hypolipidemic drug | Under clinical trials | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D041 | BioE-1115 | Biological drug | -- | -- | -- | Under clinical trials | Details |
| D142 | Fructose | Chemical drug | DB04173 | -- | Intravenous nutrition drug | Under clinical trials | Details |
| D527 | EPA/DHA | Supplement | DB11133 | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D125 | Epanova | Chemical drug | DB11133 | PPARG ligand; PPARA activator | Enhance lipid metabolism | 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 |