Novel approach using [18F]FTHA-PET and de novo synthesized VLDL for assessment of FFA metabolism in a rat model of diet induced NAFLD

Background and aims: The worldwide prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) raises concerns about associated risk factors, such as obesity and type 2 Diabetes Mellitus, for leading causes of disability and death. Besides Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS), functional imaging with Positron Emission Tomography (PET) could contribute to a deeper understanding of the pathophysiology of NAFLD. Here we describe a novel approach using the PET tracer [F-18]FTHA, which is an analog of long-chain free fatty acids (FFA) and is taken up by tissues to enter mitochondria or to be incorporated into complex lipids for further export as very-low-density lipoprotein (VLDL).Methods: Male Sprague Dawley rats, after 6 weeks on a high-fat diet (HFD), were used as a model of diet induced NAFLD, while a standard diet (SD) served as a control group. Liver fat was estimated by MR spectroscopy at a 9.4 T system for phenotyping. To measure hepatic FFA uptake, rats underwent 60 min dynamic [F-18]FTHA-PET scans after unrestricted access to food (HFD: n = 6; SD: n = 6) or overnight (=16h) fasting (HFD: n = 6; SD: n = 5). FFA removal was assessed from incorporated F-18-residual in de novo synthesized VLDL out of plasma. Results: MRS of the liver confirmed the presence of NAFLD (>5.6% fat). Under non-fasting conditions, hepatic [F-18]FTHA uptake was significantly increased in NAFLD: SUVmean (p = 0.03) within [0; 60] min interval, SUVmean (p = 0.01) and SUVmax (p = 0.03) within [30; 60] min interval. SUVs for hepatic uptake under fasting conditions were not significantly different between the groups. Analysis of FFA removal demonstrated elevated values of F-18-residue in the VLDL plasma fraction of the healthy group compared to the NAFLD (p = 0.0569).Conclusion: Our novel approach for assessing FFA metabolism using [F-18]FTHA demonstrated differences in the hepatic FFA uptake and FFA incorporation into VLDL between healthy and NAFLD rats. [F-18]FTHA-PET could be used to study metabolic disturbances involved in the progression of NAFLD. 0 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).