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

Usevalad Ustsinau; Viktoria Ehret; Clemens Fürnsinn; Thomas Scherer; Thomas H Helbich; Marcus Hacker; Martin Krššák; Cecile Philippe

doi:10.1016/j.clnu.2023.08.001

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

Clin Nutr. 2023 Oct;42(10):1839-1848. doi: 10.1016/j.clnu.2023.08.001. Epub 2023 Aug 8.

Authors

Usevalad Ustsinau¹, Viktoria Ehret², Clemens Fürnsinn², Thomas Scherer², Thomas H Helbich³, Marcus Hacker¹, Martin Krššák², Cecile Philippe⁴

Affiliations

¹ Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.
² Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
³ Division of Molecular and Structural Preclinical Imaging, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.
⁴ Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria. Electronic address: cecile.philippe@meduniwien.ac.at.

PMID: 37625314
DOI: 10.1016/j.clnu.2023.08.001

Abstract

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 [¹⁸F]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 [¹⁸F]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 ¹⁸F-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 [¹⁸F]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 ¹⁸F-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 [¹⁸F]FTHA demonstrated differences in the hepatic FFA uptake and FFA incorporation into VLDL between healthy and NAFLD rats. [¹⁸F]FTHA-PET could be used to study metabolic disturbances involved in the progression of NAFLD.

Keywords: FTHA; Free fatty acids; Metabolism; NAFLD; PET.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Type 2* / metabolism
Diet, High-Fat / adverse effects
Fatty Acids, Nonesterified
Lipoproteins, VLDL / metabolism
Liver / diagnostic imaging
Liver / metabolism
Male
Non-alcoholic Fatty Liver Disease* / diagnostic imaging
Non-alcoholic Fatty Liver Disease* / metabolism
Positron-Emission Tomography
Rats
Rats, Sprague-Dawley
Tomography, X-Ray Computed

Substances

14-fluoro-6-thiaheptadecanoic acid
Fatty Acids, Nonesterified
Lipoproteins, VLDL