hepatic mitochondrial metabolism in fatty liver disease in humans

Conditions: Non-alcoholic Fatty Liver Disease NAFLD

Summary: the goal of this clinical trial is to investigate in healthy volunteers the mechanisms by which ethanol and lipids, the two key risk factors of steatotic liver disease (sld), affect liver mitochondrial metabolism. the main question it aims to answer is: • does acute administration of ethanol and lipids increase hepatic mitochondrial reductive stress as determined by orally ingested stable isotope tracer 13c-alpha-ketoisocaproate and by plasma beta-hydroxybutyrate to acetoacetate ratio (b-ohb/acac) in humans?

in this study we investigate the effects of ethanol and lipids on hepatic mitochondrial metabolism in healthy volunteers. at first visit, an informed consent will be obtained, followed by assessment of inclusion/exclusion criteria. participants fulfilling the criteria will be enrolled in the study. body composition will be determined with bioelectrical impedance. at second visit hepatic lipid content will be measured with magnetic resonance spectroscopy. participants will be given in random order on three separate visits (3-5): * intravenous infusion of ethanol and normal saline (breath alcohol content target and upper limit corresponding to 0.6 per mil in blood) * intravenous infusions of lipid emulsion, heparin and normal saline * intravenous infusion of normal saline on study visits participant will drink a tracer dose of 13c-alpha-ketoisocaproate and l-leucine. breath samples are collected at different time points for determination of 13c enrichment of co2. furthermore "arterialized" blood samples are taken during study visits to obtain beta-hydroxybutyrate to acetoacetate ratios (b-ohb/acac) at different timepoints. whole-body oxidation of lipids, carbohydrates and protein will be determined using indirect calorimetry.

Eligibility criteria:
1. participants must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent. 2. subject must be likely to be available to complete all protocol-required study visits or procedures, to the best of the subject's and investigator's knowledge. 3. age range from 18-75 years. 4. no known hypersensitivity to egg, soy, or peanut protein, or to any of the substances of intralipid 20%, or to any other substance to be administered during the study. 5. no severe hyperlipidemia or hemophagocytotic syndrome as judged by history and physical examination and standard laboratory tests. 6. no other liver disease except for sld. 7. no advanced liver disease as judged by history and physical examination and standard laboratory tests. 8. no claustrophobia or metal implants to allow magnetic resonance studies. 9. no pregnancy or lactation in women. 10. no known or anticipated difficulties in cannulation of peripheral veins. 11. no history or evidence of any other clinically significant disorder, condition or disease other than those outlined above that, in the opinion of the investigator may compromise the ability of the subject to give written informed consent, would pose a risk to subject safety, or interfere with the study evaluation, procedures or completion. 12. no drinking problem based on audit questionnaire. 13. no use of medications interacting with alcohol. 14. no history of heparin induced thrombosytopenia (hit) or bleeding tendency. 15. no current use of warfarin, direct anticoagulants, or thrombocyte inhibitors.

Keywords: hepatic mitochondrial dysfunction mafld non-alcoholic fatty liver disease nafld 13c-α-ketoisocaproic acid breath test