Fatty Acid Synthase Inhibitor TVB-2640 Reduces Hepatic de Novo Lipogenesis in Males With Metabolic Abnormalities.
Level 4 - case-series / case-control
Single-arm phase I dose-ranging study without a control group
PubMed 31630414 · doi:10.1002/hep.31000
What was done
In an open-label phase I trial, 12 obese men (mean age 42 ± 2 years, BMI 37.4 ± 1.2 kg/m², with metabolic abnormalities and elevated liver enzymes) received the fatty acid synthase inhibitor TVB-2640 at doses of 50–150 mg/day for 10 days under controlled dietary intake. Hepatic de novo lipogenesis (DNL) was assessed before and after treatment during fasting and following an oral fructose/glucose bolus using intravenous 1-13C1-acetate labeling and gas chromatography-mass spectrometry of VLDL palmitate. Substrate oxidation and safety markers were also monitored.
What was found
Fasting hepatic DNL was reduced by up to 90% across the dose range (P = 0.003). Higher plasma concentrations of TVB-2640 correlated with reductions in fructose-stimulated peak fractional DNL (R² = -0.749, P = 0.0003) and 6-hour DNL area under the curve (R² = -0.554, P = 0.005). Combined across all subjects, alanine aminotransferase decreased by 15.8 ± 8.4% (P = 0.05). Substrate oxidation, fasting glucose, insulin, ketones, renal function, and plasma triglycerides showed no changes. Two participants experienced reversible alopecia.
Why it matters
This study provides early proof-of-mechanism in humans that pharmacological fatty acid synthase inhibition potently and dose-dependently suppresses hepatic de novo lipogenesis without increasing circulating triglycerides.
Limits
The sample size was very small (n = 12) and included only males. The treatment duration was limited to 10 days, there was no placebo control group, and direct liver histology or long-term clinical outcomes were not evaluated.
Cited by
- supports Palmitate is the primary saturated fatty acid produced by the liver via de novo lipogenesis.