Fatty Acid Synthase Inhibitor TVB‐2640 Reduces Hepatic de Novo Lipogenesis in Males With Metabolic Abnormalities

Autor: Camila Manrique-Acevedo, George Kemble, Douglas Buckley, Elizabeth J. Parks, Ayman H. Gaballah, Ghassan M. Hammoud, Majid M. Syed-Abdul, William McCulloch, Kimberlee Bingham
Rok vydání: 2020
Předmět:
Zdroj: Hepatology. 72:103-118
ISSN: 1527-3350
0270-9139
DOI: 10.1002/hep.31000
Popis: Background and aims Elevated hepatic de novo lipogenesis (DNL) is a key distinguishing characteristic of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis. In rodent models of NAFLD, treatment with a surrogate of TVB-2640, a pharmacological fatty acid synthase inhibitor, has been shown to reduce hepatic fat and other biomarkers of DNL. The purpose of this phase I clinical study was to test the effect of the TVB-2640 in obese men with certain metabolic abnormalities that put them at risk for NAFLD. Approach and results Twelve subjects (mean ± SEM, 42 ± 2 years, body mass index 37.4 ± 1.2 kg/m2 , glucose 103 ± 2 mg/dL, triacylglycerols 196 ± 27 mg/dL, and elevated liver enzymes) underwent 10 days of treatment with TVB-2640 at doses ranging from 50-150 mg/day. Food intake was controlled throughout the study. Hepatic DNL was measured before and after an oral fructose/glucose bolus using isotopic labeling with 1-13 C1 -acetate intravenous infusion, followed by measurement of labeled very low-density lipoprotein palmitate via gas chromatography mass spectometry. Substrate oxidation was measured by indirect calorimetry. Across the range of doses, fasting DNL was reduced by up to 90% (P = 0.003). Increasing plasma concentrations of TVB-2640 were associated with progressive reductions in the percent of fructose-stimulated peak fractional DNL (R2 = -0.749, P = 0.0003) and absolute DNL area under the curve 6 hours following fructose/glucose bolus (R2 = -0.554, P = 0.005). For all subjects combined, alanine aminotransferase was reduced by 15.8 ± 8.4% (P = 0.05). Substrate oxidation was unchanged, and safety monitoring revealed that the drug was well tolerated, without an increase in plasma triglycerides. Alopecia occurred in 2 subjects (reversed after stopping the drug), but otherwise no changes were observed in fasting glucose, insulin, ketones, and renal function. Conclusion These data support the therapeutic potential of a fatty acid synthase inhibitor, TVB-2640 in particular, in patients with NAFLD and nonalcoholic steatohepatitis.
Databáze: OpenAIRE
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