Research Article Details
| Article ID: | A02582 |
| PMID: | 34323067 |
| Source: | J Agric Food Chem |
| Title: | Regulation on Citrate Influx and Metabolism through Inhibiting SLC13A5 and ACLY: A Novel Mechanism Mediating the Therapeutic Effects of Curcumin on NAFLD. |
| Abstract: | Upregulated de novo lipogenesis (DNL) plays a pivotal role in the progress of the nonalcoholic fatty liver disease (NAFLD). Cytoplasmic citrate flux, mediated by plasma membrane citrate transporter (SLC13A5), mitochondrial citrate carrier (SLC25A1), and ATP-dependent citrate lyase (ACLY), determines the central carbon source for acetyl-CoA required in DNL. Curcumin, a widely accepted dietary polyphenol, can attenuate lipid accumulation in NAFLD. Here, we first investigated the lipid-lowering effect of curcumin against NAFLD in oleic and palmitic acid (OPA)-induced primary mouse hepatocytes and high-fat plus high-fructose diet (HFHFD)-induced mice. Curcumin profoundly attenuated OPA- or HFHFD-induced hyperlipidemia and aberrant hepatic lipid deposition via modulating the expression and function of SLC13A5 and ACLY. The possible mechanism of curcumin on the citrate pathway was investigated using HepG2 cells, HEK293T cells transfected with human SLC13A5, and recombinant human ACLY. In OPA-stimulated HepG2 cells, curcumin rectified the dysregulated expression of SLC13A5/ACLY possibly via the AMPK-mTOR signaling pathway. Besides, curcumin also functionally inhibited both citrate transport and metabolism mediated by SLC13A5 and ACLY, respectively. These findings confirm that curcumin improves the lipid accumulation in the liver by blocking citrate disposition and hence may be used to prevent NAFLD. |
| DOI: | 10.1021/acs.jafc.1c03105 |
| 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 |
| 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 |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T01 | 5'-AMP-activated protein kinase subunit beta-1 | PRKAB1 | activator | Kinase | Q9Y478 | AAKB1_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T46 | ATP-citrate synthase | ACLY | inhibitor | Transferase | P53396 | ACLY_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D092 | Curcumin | Chemical drug | DB11672 | PPARG; COX inhibitor | Anticancer agent; NSAID | Under clinical trials | Details |
| D142 | Fructose | Chemical drug | DB04173 | -- | Intravenous nutrition drug | Under clinical trials | Details |