Regulation on Citrate Influx and Metabolism through Inhibiting SLC13A5 and ACLY: A Novel Mechanism Mediating the Therapeutic Effects of Curcumin on NAFLD

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 inhibied 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.

https://doi.org/10.1021/acs.jafc.1c03105

Previous studies showed that Metformin is an SLC13A5 inhibitor, Gluconate is an SLC25A1 inhibitor and Hydroxycitrate is an ACLY inhibitor. A combination of SLC13A5, SLC25A1 and ACLY inhibitors may be necessary to adequately reduce citrate levels in the tumor environment.

Citrate transporter inhibitors: possible new anticancer agents

Combination of mitochondrial and plasma membrane citrate transporter inhibitors inhibits de novo lipogenesis pathway and triggers apoptosis