PHARMACOLOGICAL RESEARCH
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2025
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IF 10.5
Mengdi Zhang,Jinliang Ji,Yuanyuan Lei,Fujian Qin,Yitong Tao,Ning Li,Jinlei Bian,Zhiyu Li,Maode Lai,Zhixia Qiu
Inhibiting de novo lipogenesis (DNL) in hepatocytes is a promising strategy for treating metabolic fatty liver diseases. ACLY, a key enzyme in the DNL pathway, has become a therapeutic target for non-alcoholic fatty liver disease (NAFLD). However, its inhibition shows mixed outcomes, depending on interventions and diets. Evidence suggest ACLY inhibition activates the ACSS2-mediated acetate metabolism and the subsequent DNL, though potential mechanisms and possible consequences remain unclear. This study found that targeting hepatic ACLY with AAV8-shRNA failed to improve NAFLD in mice fed a high-fat, high-fructose diet. Instead, it worsened inflammation and liver injury. ACLY inhibition conditionally upregulated DNL enzymes, but consistently activated the ACSS2-acetyl-CoA pathway and suppressed fatty acid oxidation. Further, ACLY inhibition led to polyunsaturated fatty acid accumulation, triggering mitochondrial dysfunction. The resulting ROS redirected carbon flux into acetate, activating the ACSS2-acetyl-CoA pathway, which promoted lipid biosynthesis and exacerbated mitochondrial dysfunction—a vicious cycle that fueled inflammation and liver damage. Dual inhibition of ACLY and ACSS2 broke this cycle by reducing hepatic acetyl-CoA flux, suppressing DNL, enhancing fatty acid oxidation via PPAR-α activation, and improving mitochondrial function. This combined targeting strategy reduced lipid accumulation, alleviated inflammation, and normalized aminotransferase levels, effectively reversing NAFLD progression.
研究领域:
生物化学
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代谢疾病
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肝脏研究
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DOI
PubMed
高影响因子
FITOTERAPIA
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2025
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IF 2.6
Yao Wang,Pan Wang,Fangfang Xu,Han Zhou,Xiaomin Xie,Tao Hou,Fengbin Luo,Yuchang Sun,Yanfang Liu,Jixia Wang,Dongmei Fu
ATP citrate lyase (ACLY) is a crucial enzyme in glycolipid metabolism. To date, only its one prodrug bempedoic acid has been approved. The discovery of direct ACLY inhibitors is important for developing new lipid-lowering drugs. Grape seeds, used in functional foods and medicines, have lipid-lowering efficacy. However, it remains unknown whether their components directly inhibit ACLY. To investigate it, a multi-component screening method was used and proanthocyanidin B2 was identified as a novel ACLY inhibitor with an IC 50 value of 2.73 μM. Differential scanning fluorimetry confirmed its directly binding to ACLY. Proanthocyanidin B2 acted as a noncompetitive inhibitor in kinetic studies and bound stably with ACLY in molecular dynamics simulations. In vitro , proanthocyanidin B2 reduced lipid accumulation via inhibiting key transcription factors associated with ACLY. This study revealed a novel ACLY inhibitor contributing to lipid-lowering efficacy of grape seeds and provided a unique scaffold for ACLY drug design.
研究领域:
生物化学
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药理学
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分子生物学
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天然产物化学
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代谢疾病
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药物发现
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DOI
PubMed
高影响因子
Cell Death & Disease
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2024
·Vol. 15
·期 7
·1-17
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IF 8.1
Wang Yuying,Su Kunqi,Wang Chang,Deng Tao,Liu Xiaofeng,Sun Shiqi,Jiang Yang,Zhang Chunfeng,Xing Baocai,Du Xiaojuan
Chemotherapeutic efficacy is seriously impeded by chemoresistance in more than half of hepatocellular carcinoma (HCC) patients. However, the mechanisms involved in chemotherapy-induced upregulation of chemoresistant genes are not fully understood. Here, this study unravels a novel mechanism controlling nuclear acetyl-CoA production to activate the transcription of chemoresistant genes in HCC. NAT10 is upregulated in HCC tissues and its upregulation is correlated with poor prognosis of HCC patients. NAT10 is also upregulated in chemoresistant HCC cells. Targeting NAT10 increases the cytotoxicity of chemotherapy in HCC cells and mouse xenografts. Upon chemotherapy, NAT10 translocates from the nucleolus to the nucleus to activate the transcription of CYP2C9 and PIK3R1 . Additionally, nuclear acetyl-CoA is specifically upregulated by NAT10. Mechanistically, NAT10 binds with ACLY in the nucleus and acetylates ACLY at K468 to counteract the SQSTM1-mediated degradation upon chemotherapy. ACLY K468-Ac specifically accumulates in the nucleus and increases nuclear acetyl-CoA production to activate the transcription of CYP2C9 and PIK3R1 through enhancing H3K27ac. Importantly, K468 is required for nuclear localization of ACLY. Significantly, ACLY K468-Ac is upregulated in HCC tissues, and ablation of ACLY K468-Ac sensitizes HCC cells and mouse xenografts to chemotherapy. Collectively, these findings identify NAT10 as a novel chemoresistant driver and the blockage of NAT10-mediated ACLY K468-Ac possesses the potential to attenuate HCC chemoresistance.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2024
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IF 8
Yilin Zhao,Amin Zhang,Shuyun Feng,Tiantian Liu,Jingjing Ning,Yucai Zhang,Jin Cheng,Qian Zhang,Chunxia Wang
Sepsis is a critical condition characterized by high morbidity and mortality. The development of technologies for early recognition of sepsis is essential for enhancing patient outcomes. Our original finding indicates that ATP-citrate lyase (ACLY) holds promise as a diagnostic biomarker for sepsis; however, sensitive methods for detecting trace levels of ACLY in serum are currently lacking. We have therefore developed a novel AP-M@Anti ACLY detection probe based on surface-enhanced Raman scattering (SERS) for the detection of serum ACLY. The AuNBPs@MBA was synthesized using gold nanobipyramids (AuNBPs) as the base and 4-mercaptobenzoic acid (4-MBA) as a reflective indicator for ACLY activity. Specifically, the Raman signal of 4-MBA decreases proportionally with an increase in ACLY concentration. ACLY antibodies were subsequently linked to AuNBPs@MBA via the gold-sulfur bonds and blocked with bovine serum albumin (BSA). Under optimized conditions, the probe exhibits a strong linear correlation between Raman signal and ACLY concentrations, ranging from 1 pg/mL - 0.5 ng/mL (R 2 = 0.998) and 0.1–500 ng/mL (R 2 = 0.999), with a remarkable limit of detection (LOD) of 1.0 pg/mL. AP-M@Anti ACLY detection probe surpasses enzyme-linked immunosorbent assay (ELISA) when testing septic children's serum samples in terms of its detection range, accuracy, and analysis time. Recovery rates ranged from 96.80 % to 102.52 %. In conclusion, all results suggest that AP-M@Anti ACLY detection probe is a promising tool for the early diagnosis of sepsis and offers new insights into the development of preclinical approaches.
研究领域:
医学诊断
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纳米技术
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生物传感器
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临床化学
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儿科
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传染病学
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DOI
高影响因子
LIFE SCIENCES
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2025
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IF 5.1
Wen Zhang,Manzhi Qi,Xiaojing Zhao,Ying Zhong,Weilong Xu,Liang Sheng,Liu Yang
Background Hepatic steatosis is a hallmark of alcohol-associated liver disease (ALD) and interacts with hepatic inflammation to drive disease progression. NF-κB-inducing kinase (NIK) has been established as a bridge linking inflammation to steatosis in ALD. Intriguingly, while hepatocyte-specific NIK deficiency attenuated ALD in the chronic-plus-binge model, it paradoxically exacerbated the disease under chronic ethanol exposure, suggesting a complex, context-dependent role for NIK. Methods To elucidate the mechanism underlying this protective effect in chronic ethanol exposure, we employed transcriptomics and proteomics analyses in hepatocyte-specific NIK knockout (NIK Δhep ) mice. Key findings were validated using immunoblotting, co-immunoprecipitation, and loss-of-function experiments both in vivo and in vitro. Results We demonstrated that NIK deficiency activated AKT, enhancing ATP-citrate lyase (ACLY)-mediated lipogenesis. Transcriptomics and proteomic screening identified inositol polyphosphate-5-phosphatase B (INPP5B) as the critical mediator suppressing AKT signaling downstream of NIK. Furthermore, we mechanistically established that NIK stabilizes INPP5B by recruiting it into the adaptor protein APPL1 complex, thereby reducing its ubiquitination and subsequent degradation. Conclusion Our study unveils a novel protective dimension of NIK, whereby it ameliorates chronic ethanol-induced hepatic steatosis by stabilizing INPP5B to suppress the AKT/ACLY lipogenic pathway. This finding provides a crucial mechanistic explanation for the context-dependent functions of NIK in ALD and redefines its role as a potential metabolic safeguard in chronic liver disease.
研究领域:
分子生物学
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肝病学
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代谢性疾病
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信号转导
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酒精研究
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
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2023
·Vol. 51
·期 12
·1628-1641
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IF 3.9
Qiushuang Sun,Yating Guo,Wenjun Hu,Mengdi Zhang,Shijiao Wang,Yuanyuan Lei,Haitao Meng,Ning Li,Pengfei Xu,Zhiyu Li,Haishu Lin,Fang Huang,Zhixia Qiu
The hepatic SLC13A5/SLC25A1-ATP–dependent citrate lyase (ACLY) signaling pathway, responsible for maintaining the citrate homeostasis, plays a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Bempedoic acid (BA), an ACLY inhibitor commonly used for managing hypercholesterolemia, has shown promising results in addressing hepatic steatosis. This study aimed to elucidate the intricate relationships in processes of hepatic lipogenesis among SLC13A5, SLC25A1, and ACLY and to examine the therapeutic potential of BA in NAFLD, providing insights into its underlying mechanism. In murine primary hepatocytes and HepG2 cells, the silencing or pharmacological inhibition of SLC25A1/ACLY resulted in significant upregulation of SLC13A5 transcription and activity. This increase in SLC13A5 activity subsequently led to enhanced lipogenesis, indicating a compensatory role of SLC13A5 when the SLC25A1/ACLY pathway was inhibited. However, BA effectively counteracted this upregulation, reduced lipid accumulation, and ameliorated various biomarkers of NAFLD. The disease-modifying effects of BA were further confirmed in NAFLD mice. Mechanistic investigations revealed that BA could reverse the elevated transcription levels of SLC13A5 and ACLY, and the subsequent lipogenesis induced by PXR activation in vitro and in vivo. Importantly, this effect was diminished when PXR was knocked down, suggesting the involvement of the hepatic PXR-SLC13A5/ACLY signaling axis in the mechanism of BA action. In conclusion, SLC13A5-mediated extracellular citrate influx emerges as an alternative pathway to SLC25A1/ACLY in the regulation of lipogenesis in hepatocytes, BA exhibits therapeutic potential in NAFLD by suppressing the hepatic PXR-SLC13A5/ACLY signaling axis, while PXR, a key regulator in drug metabolism may be involved in the pathogenesis of NAFLD.
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2021
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IF 5.279
Qiushuang Sun,Qun Niu,Yating Guo,Yu Zhuang,Xiaonan Li,Jia Liu,Ning Li,Zhiyu Li,Fang Huang,Zhixia Qiu
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.
研究领域:
药理学
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分子生物学
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代谢紊乱
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2024
·Vol. 43
·期 1
·1-27
·
IF 11.4
Shan Junqi,Li Xinyu,Sun Runqi,Yao Yao,Sun Yan,Kuang Qin,Dai Xianling,Sun Yanlai
Background The failure of proper recognition of the intricate nature of pathophysiology in colorectal cancer (CRC) has a substantial effect on the progress of developing novel medications and targeted therapy approaches. Imbalances in the processes of lipid oxidation and biosynthesis of fatty acids are significant risk factors for the development of CRC. Therapeutic intervention that specifically targets the peroxisome proliferator-activated receptor gamma (PPARγ) and its downstream response element, in response to lipid metabolism, has been found to promote the growth of tumors and has shown significant clinical advantages in cancer patients. Methods Clinical CRC samples and extensive in vitro and in vivo experiments were carried out to determine the role of ZDHHC6 and its downstream targets via a series of biochemical assays, molecular analysis approaches and lipid metabolomics assay, etc. Results To study the effect of ZDHHC6 on the progression of CRC and identify whether ZDHHC6 is a palmitoyltransferase that regulates fatty acid synthesis, which directly palmitoylates and stabilizes PPARγ, and this stabilization in turn activates the ACLY transcription-related metabolic pathway. In this study, we demonstrate that PPARγ undergoes palmitoylation in its DNA binding domain (DBD) section. This lipid-related modification enhances the stability of PPARγ protein by preventing its destabilization. As a result, palmitoylated PPARγ inhibits its degradation induced by the lysosome and facilitates its translocation into the nucleus. In addition, we have identified zinc finger-aspartate-histidine-cysteine 6 (ZDHHC6) as a crucial controller of fatty acid biosynthesis. ZDHHC6 directly interacts with and adds palmitoyl groups to stabilize PPARγ at the Cys-313 site within the DBD domain of PPARγ. Consequently, this palmitoylation leads to an increase in the expression of ATP citrate lyase (ACLY). Furthermore, our findings reveals that ZDHHC6 actively stimulates the production of fatty acids and plays a role in the development of colorectal cancer. However, we have observed a significant reduction in the cancer-causing effects when the expression of ZDHHC6 is inhibited in in vivo trials. Significantly, in CRC, there is a strong positive correlation between the high expression of ZDHHC6 and the expression of PPARγ. Moreover, this high expression of ZDHHC6 is connected with the severity of CRC and is indicative of a poor prognosis. Conclusions We have discovered a mechanism in which lipid biosynthesis is controlled by ZDHHC6 and includes the signaling of PPARγ-ACLY in the advancement of CRC. This finding provides a justification for targeting lipid synthesis by blocking ZDHHC6 as a potential therapeutic approach.
研究领域:
癌症生物学
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分子生物学
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脂质代谢
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
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