Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement
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 in...
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Elsevier
2025-05-01
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| author | Mengdi Zhang Jinliang Ji Yuanyuan Lei Fujian Qin Yitong Tao Ning Li Jinlei Bian Zhiyu Li Maode Lai Zhixia Qiu |
| author_facet | Mengdi Zhang Jinliang Ji Yuanyuan Lei Fujian Qin Yitong Tao Ning Li Jinlei Bian Zhiyu Li Maode Lai Zhixia Qiu |
| author_sort | Mengdi Zhang |
| collection | DOAJ |
| description | 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 suggests 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. |
| format | Article |
| id | doaj-art-5a2fb4c75aeb4ed4892dea34cf53aba9 |
| institution | DOAJ |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
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| series | Pharmacological Research |
| spelling | doaj-art-5a2fb4c75aeb4ed4892dea34cf53aba92025-08-20T03:14:08ZengElsevierPharmacological Research1096-11862025-05-0121510770610.1016/j.phrs.2025.107706Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancementMengdi Zhang0Jinliang Ji1Yuanyuan Lei2Fujian Qin3Yitong Tao4Ning Li5Jinlei Bian6Zhiyu Li7Maode Lai8Zhixia Qiu9School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaSchool of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaNational Experimental Teaching Demonstration Center of Pharmacy, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Corresponding authors.School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China; Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China; Corresponding author at: School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Corresponding authors.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 suggests 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.http://www.sciencedirect.com/science/article/pii/S1043661825001318Non-alcoholic fatty liver disease (NAFLD)De novo lipogenesis (DNL)ATP citrate lyase (ACLY)Acyl-coenzyme A synthetase short-chain family member 2 (ACSS2)Acetyl-CoAFatty acid oxidation |
| spellingShingle | Mengdi Zhang Jinliang Ji Yuanyuan Lei Fujian Qin Yitong Tao Ning Li Jinlei Bian Zhiyu Li Maode Lai Zhixia Qiu Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement Pharmacological Research Non-alcoholic fatty liver disease (NAFLD) De novo lipogenesis (DNL) ATP citrate lyase (ACLY) Acyl-coenzyme A synthetase short-chain family member 2 (ACSS2) Acetyl-CoA Fatty acid oxidation |
| title | Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement |
| title_full | Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement |
| title_fullStr | Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement |
| title_full_unstemmed | Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement |
| title_short | Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement |
| title_sort | dual inhibition of hepatic acly and acss2 a synergistic approach to combat nafld through lipogenesis reduction and mitochondrial enhancement |
| topic | Non-alcoholic fatty liver disease (NAFLD) De novo lipogenesis (DNL) ATP citrate lyase (ACLY) Acyl-coenzyme A synthetase short-chain family member 2 (ACSS2) Acetyl-CoA Fatty acid oxidation |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825001318 |
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