Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California at Berkeley, Berkeley, CA, USA.
Gilead Sciences, Inc, Foster City, CA, USA.
J Lipid Res. 2023 Mar;64(3):100339. doi: 10.1016/j.jlr.2023.100339. Epub 2023 Feb 2.
Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4-45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy.
在非酒精性脂肪性肝炎（NASH）中使用乙酰辅酶 A 羧化酶抑制剂（ACCi）治疗可能会增加血浆甘油三酯（TGs），载脂蛋白 B（apoB）浓度也会发生变化。ACC 是从头合成脂肪和调节脂肪酸氧化的限速酶，使其成为 NASH 有吸引力的治疗靶点。我们的目的是确定 ACCi 法西司他汀对 NASH 患者血浆 LDL-apoB 产生率的影响，以及与非诺贝特联合治疗的效果。在 16 名接受法西司他汀治疗 12 周的 NASH 患者和 29 名接受法西司他汀和非诺贝特治疗 12 周的 NASH 受试者中，使用重水代谢标记和 LDL-apoB 富集的串联质谱分析进行了研究。在接受法西司他汀治疗的 NASH 患者中，血浆 TG 从基线到第 12 周显著增加了 17%（P = 0.0056）。LDL-apoB 分数替代率（基线至第 12 周：31 ± 20.2%至 46 ± 22.6%/天，P = 0.03）和绝对合成率（ASR）（30.4-45.2 mg/dl/天，P = 0.016）也有显著增加，但血浆 apoB 浓度没有增加。法西司他汀对 LDL-apoB ASR 的影响仅限于肝硬化患者（基线时为 21.0 ± 9.6，第 12 周时为 44.2 ± 17 mg/dl/天，P = 0.002，N = 8）；非肝硬化患者没有变化（分别为 39.8 ± 20.8 和 46.3 ± 14.8 mg/dl/天，P = 0.51，N = 8）。非诺贝特和法西司他汀联合治疗可预防血浆 TG、LDL-apoB 分数替代率和 ASR 的增加。总之，在肝硬化的 NASH 中，ACCi 治疗会增加 LDL-apoB100 的产生率，而同时使用非诺贝特治疗可以预防这种作用。
