Research Article Details
| Article ID: | A44194 |
| PMID: | 29465311 |
| Source: | FASEB J |
| Title: | p32 regulates ER stress and lipid homeostasis by down-regulating GCS1 expression. |
| Abstract: | Sustained endoplasmic reticulum (ER) stress plays a major role in the development of many metabolic diseases, including cardiovascular disease, nonalcoholic fatty liver disease, insulin resistance, obesity, and diabetes. p32 is a multicompartmental protein involved in the regulation of oxidative phosphorylation and glucose oxidation. p32 ablation is associated with resistance to age-associated and diet-induced obesity through a mechanism that remains largely unknown. Here, we show that p32 promotes lipid biosynthesis by modulating fatty acid-induced ER stress. We found that p32 interacts with endoplasmic reticulum-anchored enzyme mannosyl-oligosaccharide glucosidase I (GCS1), an ER lumen-anchored glucosidase that is essential for the processing of N-linked glycoproteins, and reduces GCS1 in a lysosome-dependent manner. We demonstrate that increased GCS1 expression alleviates fatty acid-induced ER stress and is critical for suppressing ER stress-associated lipogenic gene activation, as demonstrated by the down-regulation of Srebp1, Fasn, and Acc. Consistently, suppression of p32 leads to increased GCS1 expression and alleviates fatty acid-induced ER stress, resulting in reduced lipid accumulation. Thus, p32 and GCS1 are regulators of ER function and lipid homeostasis and are potential therapeutic targets for the treatment of obesity and diabetes.-Liu, Y., Leslie, P. L., Jin, A., Itahana, K., Graves, L. M., Zhang, Y. p32 regulates ER stress and lipid homeostasis by down-regulating GCS1 expression. |
| DOI: | 10.1096/fj.201701004RR |
| 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 |
| 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 |