Acetyl-CoA carboxylase inhibitor increases LDL-apoB production rate in NASH with cirrhosis: prevention by fenofibrate

• Published in: Journal of lipid research Vol. 64; no. 3; p. 100339
• Main Authors: Dandan, Mohamad, Han, Julia, Mann, Sabrina, Kim, Rachael, Li, Kelvin, Mohammed, Hussein, Chuang, Jen-Chieh, Zhu, Kaiyi, Billin, Andrew N., Huss, Ryan S., Chung, Chuhan, Myers, Robert P., Hellerstein, Marc
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2023; American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Acetyl-CoA Carboxylase; Apolipoproteins B; fenofibrate; Fenofibrate - pharmacology; Fenofibrate - therapeutic use; firsocostat; Humans; hypertriglyceridemia; LDL; lipoproteins; lipoproteins/kinetics; lipoproteins/metabolism; Liver Cirrhosis - drug therapy; mass spectrometry; Non-alcoholic Fatty Liver Disease - drug therapy; nonalcoholic steatohepatitis; Patient-oriented and Epidemiological Research; Triglycerides; ASR; ACC; MRE; NAFLD; DNL; FRR; hypertriglyceridemia; triglycerides; NASH; nonalcoholic steatohepatitis; TG; LDL; ACCi; lipoproteins/kinetics; mass spectrometry; fenofibrate; lipoproteins/metabolism; lipoproteins; firsocostat
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1016/j.jlr.2023.100339

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. Graphical abstract: ACCi treatment alone (green arrow) leads to increased apoB particle production in the liver as shown by increased production of LDL-apoB. Fenofibrate combined with ACCi treatment (red inhibitory symbol) prevented the increased LDL-apoB particle production. [Display omitted]