Research Article Details
| Article ID: | A19356 |
| PMID: | 26609894 |
| Source: | Expert Opin Ther Targets |
| Title: | Pathophysiological mechanisms and therapeutic potentials of macrophages in non-alcoholic steatohepatitis. |
| Abstract: | INTRODUCTION: Non-alcoholic steatohepatitis (NASH), a hepatic manifestation of metabolic syndrome, is a major cause of morbidity and healthcare burden worldwide. While the molecular pathogenesis of NASH remains unclear and therapeutic options are limited, inflammation is recognized as an essential factor for NASH development. Factors that link NASH to inflammation are macrophages and their secreted cytokines. AREAS COVERED: This review summarizes the current knowledge of macrophage-mediated molecular pathways in NASH to shed insights on potential pharmacotherapeutic applications. EXPERT OPINION: Macrophages are not only known for their role of phagocytosis in innate immunity, but also for both extrinsic and intrinsic regulation of inflammatory functions of many cytokines. Recent advances have revealed the effects of macrophage recruitment and polarization on the development of NASH. We and others have shown that the proliferation of hepatic macrophages and the subsequent production of pro-inflammatory cytokines initiates inflammatory cascades, orchestrates activities of transcription factors involved in lipid metabolism/translocation, and modulates programmed cell death. Together, these findings support the pathophysiological role of macrophages in the pathogenesis of NASH. Thus, evaluating potential therapeutic targets against the infiltration and/or polarization of specific macrophage subtypes is of clinical interest for alleviation of early-stage NASH, with the goal of halting disease progression. |
| DOI: | 10.1517/14728222.2016.1125883 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| 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 |
| S13 | Anti-apoptosis | hepatocyte apoptosis; hepatic autophagy; apoptosis | Pan-caspase inhibitor | Emricasan | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name |
|---|
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |