Hepatic Mitochondrial Metabolism in Fatty Liver Disease in Humans

NCT06559878 | Enrolling By Invitation

• 1 other identifier: HUS/8748/2023
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief 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?

Conditions

Non-alcoholic Fatty Liver Disease NAFLD

Keywords

Hepatic mitochondrial dysfunction; MAFLD; Non-alcoholic Fatty Liver Disease NAFLD; 13C-α-Ketoisocaproic Acid Breath Test

Outcome Measures

Primary Outcomes (2)

• Change in arterialized plasma b-OHB to AcAc ratio

  Arterialized plasma b-OHB and AcAc concentrations

  From baseline to the end of treatment at 240 minutes

• Breath 13CO2 enrichment after ingesting 13C-alpha-ketoisocaproate

  Measured as area under the curve

  From baseline to the end of treatment at 330 minutes.

Other Outcomes (1)

• Plasma metabolomics

  From baseline until the end of treatment at 240 minutes.

Study Arms (6)

The order of metabolic visits: 1.Normal saline, 2.Lipid emulsion, 3.Ethanol

EXPERIMENTAL

Diagnostic Test: 13C-α-Ketoisocaproic Acid Breath Test; Dietary Supplement: Ethanol; Dietary Supplement: Lipid Emulsion; Other: Normal Saline

The order of metabolic visits: 1. Normal saline, 2. Ethanol, 3. Lipid emulsion

EXPERIMENTAL

Diagnostic Test: 13C-α-Ketoisocaproic Acid Breath Test; Dietary Supplement: Ethanol; Dietary Supplement: Lipid Emulsion; Other: Normal Saline

The order of metabolic visits: 1.Lipid emulsion, 2.Normal saline, 3.Ethanol

EXPERIMENTAL

Diagnostic Test: 13C-α-Ketoisocaproic Acid Breath Test; Dietary Supplement: Ethanol; Dietary Supplement: Lipid Emulsion; Other: Normal Saline

The order of metabolic visits: 1.Lipid emulsion, 2.Ethanol, 3.Normal saline

EXPERIMENTAL

Diagnostic Test: 13C-α-Ketoisocaproic Acid Breath Test; Dietary Supplement: Ethanol; Dietary Supplement: Lipid Emulsion; Other: Normal Saline

The order of metabolic visits: 1. Ethanol, 2. Normal saline, 3. Lipid emulsion

EXPERIMENTAL

Diagnostic Test: 13C-α-Ketoisocaproic Acid Breath Test; Dietary Supplement: Ethanol; Dietary Supplement: Lipid Emulsion; Other: Normal Saline

The order of metabolic visits: 1. Ethanol, 2. Lipid emulsion, 3. Normal saline

EXPERIMENTAL

Diagnostic Test: 13C-α-Ketoisocaproic Acid Breath Test; Dietary Supplement: Ethanol; Dietary Supplement: Lipid Emulsion; Other: Normal Saline

Interventions

13C-α-Ketoisocaproic Acid Breath Test DIAGNOSTIC_TEST

13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).

The order of metabolic visits: 1. Ethanol, 2. Lipid emulsion, 3. Normal saline; The order of metabolic visits: 1. Ethanol, 2. Normal saline, 3. Lipid emulsion; The order of metabolic visits: 1. Normal saline, 2. Ethanol, 3. Lipid emulsion; The order of metabolic visits: 1.Lipid emulsion, 2.Ethanol, 3.Normal saline; The order of metabolic visits: 1.Lipid emulsion, 2.Normal saline, 3.Ethanol; The order of metabolic visits: 1.Normal saline, 2.Lipid emulsion, 3.Ethanol

Ethanol DIETARY_SUPPLEMENT

6% ethanol soluted in normal saline is given intravenously during one metabolic visit.

Also known as: Alcohol

The order of metabolic visits: 1. Ethanol, 2. Lipid emulsion, 3. Normal saline; The order of metabolic visits: 1. Ethanol, 2. Normal saline, 3. Lipid emulsion; The order of metabolic visits: 1. Normal saline, 2. Ethanol, 3. Lipid emulsion; The order of metabolic visits: 1.Lipid emulsion, 2.Ethanol, 3.Normal saline; The order of metabolic visits: 1.Lipid emulsion, 2.Normal saline, 3.Ethanol; The order of metabolic visits: 1.Normal saline, 2.Lipid emulsion, 3.Ethanol

Lipid Emulsion DIETARY_SUPPLEMENT

Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.

The order of metabolic visits: 1. Ethanol, 2. Lipid emulsion, 3. Normal saline; The order of metabolic visits: 1. Ethanol, 2. Normal saline, 3. Lipid emulsion; The order of metabolic visits: 1. Normal saline, 2. Ethanol, 3. Lipid emulsion; The order of metabolic visits: 1.Lipid emulsion, 2.Ethanol, 3.Normal saline; The order of metabolic visits: 1.Lipid emulsion, 2.Normal saline, 3.Ethanol; The order of metabolic visits: 1.Normal saline, 2.Lipid emulsion, 3.Ethanol

Normal Saline OTHER

Normal saline is given intravenously during one metabolic visit.

The order of metabolic visits: 1. Ethanol, 2. Lipid emulsion, 3. Normal saline; The order of metabolic visits: 1. Ethanol, 2. Normal saline, 3. Lipid emulsion; The order of metabolic visits: 1. Normal saline, 2. Ethanol, 3. Lipid emulsion; The order of metabolic visits: 1.Lipid emulsion, 2.Ethanol, 3.Normal saline; The order of metabolic visits: 1.Lipid emulsion, 2.Normal saline, 3.Ethanol; The order of metabolic visits: 1.Normal saline, 2.Lipid emulsion, 3.Ethanol

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

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.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Helsinki University Central Hospital: lead

Study Sites (1)

Helsinki Central University Hospital

Helsinki, Uusimaa, 00290, Finland

Location

MeSH Terms

Interventions

Ethanol; Fat Emulsions, Intravenous; Saline Solution

Intervention Hierarchy (Ancestors)

Alcohols; Organic Chemicals; Emulsions; Colloids; Dosage Forms; Pharmaceutical Preparations; Parenteral Nutrition Solutions; Pharmaceutical Solutions; Solutions; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Specialty Uses of Chemicals; Crystalloid Solutions; Isotonic Solutions

Study Officials

• Panu Luukkonen, MD, PhD

  Helsinki University Central Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Model Details: The study protocol includes five clinical visits. 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. At second visit, magnetic resonance studies will be performed to quantify liver fat content. Visits 3-5 consist of metabolic studies using the 13C-ketoisocaproate breath test and, in a random order, infusions of either a) saline alone, b) saline, a lipid emulsion and heparin or c) saline and ethanol.

Study Record Dates

• First Submitted: August 12, 2024
• First Posted: August 19, 2024
• Study Start: September 1, 2024
• Primary Completion: February 28, 2026
• Study Completion (Estimated): January 31, 2027
• Last Updated: August 19, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

FI (1)