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

Sun, Qian; Niu, Qun; Guo, Yating; Zhuang, Yu; Li, Xiaonan; Liu, Jia; Li, Ning; Li, Zhiyu; Huang, Fang; Qiu, Zhixia

doi:10.1021/acs.jafc.1c03105

Cited by 21 publications

(15 citation statements)

References 35 publications

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“…It also inhibits HMGB1-NF-κB translocation, macrophage M1 polarization, and inflammatory factor secretion to reduce liver damage. Cur can alleviate NASH by upregulating the Nrf2 gene, protecting mitochondria, and reducing apoptosis. , Additionally, Cur improves hepatic lipid accumulation to curb NASH development through the AMPK-mTOR signaling pathway . THC is reported to protect against NAFLD by reducing adipogenesis, activating AMP-activated protein kinase, and increasing fatty acid oxidation .…”

Section: Discussionmentioning

confidence: 99%

Curcumin Alleviates High-fat Diet-induced Nonalcoholic Steatohepatitis via Improving Hepatic Endothelial Function with Microbial Biotransformation in Rats

Huang

et al. 2023

J. Agric. Food Chem.

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Hepatic endothelial function is central to the development of nonalcoholic steatohepatitis (NASH). Curcumin (Cur) is reportedly hepatoprotective, however, it remains unknown whether Cur improves hepatic endothelial function in NASH. Additionally, the poor bioavailability of Cur renders it difficult to elucidate its hepatoprotective effect, hence, its biotransformation should be considered. Herein, we investigated the effects and mechanisms of Cur and its bioconversion on hepatic endothelial function against high-fat diet-induced NASH in rats. The results revealed that Cur improved hepatic lipid accumulation, inflammation, and endothelial dysfunction by inhibiting NF-κB and PI3K/Akt/HIF-1α pathways, however, these effects were weakened via antibiotic addition, which was closely related to reduced tetrahydrocurcumin (THC) produce in the liver and intestinal content. Moreover, THC exerted a better effect than Cur on restoring liver sinusoidal endothelial cells function to attenuate steatosis and injury in L02 cells. Thus, these findings indicate that the effect of Cur on NASH is closely related to hepatic endothelial function improvement with intestinal microbial biotransformation.

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Section: Discussionmentioning

confidence: 99%

Curcumin Alleviates High-fat Diet-induced Nonalcoholic Steatohepatitis via Improving Hepatic Endothelial Function with Microbial Biotransformation in Rats

Huang

et al. 2023

J. Agric. Food Chem.

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“…Therefore, targeting multiple metabolic pathways may be a more effective strategy. Our group previously reported that curcumin, a natural product, regulates hepatocyte citrate flux by directly inhibiting the function of SLC13A5 and ACLY and indirectly regulating the expression of SLC13A5 and ACLY by activating the AMPK–mTOR signaling pathway to treat hyperlipidemia . Several studies have found that a compensatory increase in acetate occurs when the source of citrate was reduced. , Acetyl-CoA synthetase 2 (ACSS2) can convert acetate to acetyl-CoA and supplement the carbon source required for lipid synthesis under certain conditions .…”

Section: Future Perspectivesmentioning

confidence: 99%

Opportunities and Challenges for Inhibitors Targeting Citrate Transport and Metabolism in Drug Discovery

Zhang

Qiu

et al. 2023

J. Med. Chem.

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Lipid metabolism disorder is closely related to metabolic diseases, inflammation, and cancer. The concentration of citrate in the cytosol has a significant impact on lipid synthesis. The expression of citrate transporters (SLC13A5 and SLC25A1) and metabolic enzymes (ACLY) proves to be substantially raised in various diseases related to disorders of lipid metabolism, such as hyperlipemia, nonalcoholic fatty liver disease, and prostate cancer. Targeting key proteins in the citrate transport and metabolic pathways is considered an effective strategy for treating various metabolic diseases. However, there is currently only one ACLY inhibitor approved for marketing, and no SLC13A5 inhibitor has entered clinical research. Further development of drugs targeting citrate transport and metabolism is needed for the treatment of metabolic diseases. This perspective summarizes the biological role, therapeutic potential, and research progress of citrate transport and metabolism and then discusses the achievements and prospects of modulators targeting citrate transport and metabolism for therapeutic applications.

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“…Curcumin has significant lipid lowering effect and inhibit the overexpression of SLC13A5 and ACLY. This further reduces the upregulation of de novo lipogenesis and regulates the lipid accumulation in NAFLD in mice [64]. The hydroxy citric acid extract from the Garcinia cambogia was evaluated for the inflammatory, atherogenic and metabolic biomarkers in 40 obese women with NAFLD.…”

Section: Role Of Citrate In Fatty Liver Diseasementioning

confidence: 99%

Role of Sodium dependent SLC13 transporter and its inhibitors in various metabolic disorders

Akhtar

Khan

Kumar

et al. 2022

Preprint

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The sodium dependent SLC13 family transporters comprise of the five genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5 (NaCT). Among them the three NaDC1, NaDC3 and NaCT are sodium dependent transporters such as di-carboxylates (succinate, malate, α-ketoglutarate) and tricarboxylates (citrate). The mouse and the human NaCT structures have still not been crystallized, the information to the structures is taken from the related bacterial transporter of VcINDY. Citrate in the cytosol works as precursor for the fatty acid synthesis, cholesterol, and low-density lipoproteins. The excess citrate from the matrix is translocated to the cytosol for fatty acid synthesis through these receptors and thus controls the energy balance by downregulating the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown. These transporters play an important role in regulating various metabolic diseases including cancer, diabetes, obesity, fatty liver diseases and CNS disorders. These di and tricarboxylate transporters are emerging as new targets for metabolic disorders such as obesity and diabetes. The mutation in the function of the NaCT causes several neurological diseases including neonatal epilepsy and impaired brain development whereas mutation of the citrate present in the liver may provide positive effect. Therefore, continued efforts from the earlier work on citrate transporter are required for the development of citrate inhibitors. In this review the structure, function, and regulation of the NaCT receptors are discussed. The review also highlights citrate role in diagnosing diseases such as cancer, diabetes, fatty liver, and diabetes. The therapeutic perspective of synthetic inhibitors against NaCT receptors are succinctly summarized.

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

Cited by 21 publications

References 35 publications

Curcumin Alleviates High-fat Diet-induced Nonalcoholic Steatohepatitis via Improving Hepatic Endothelial Function with Microbial Biotransformation in Rats

Curcumin Alleviates High-fat Diet-induced Nonalcoholic Steatohepatitis via Improving Hepatic Endothelial Function with Microbial Biotransformation in Rats

Opportunities and Challenges for Inhibitors Targeting Citrate Transport and Metabolism in Drug Discovery

Role of Sodium dependent SLC13 transporter and its inhibitors in various metabolic disorders

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