Kinetics of Metabolic Cofactors in NAFLD (NAFLDCOFCAL)

Kinetics of Metabolic Cofactors After Oral Supplementation in Healthy Subjects

There is a strong correlation between major adverse health consequences of obesity and development of non-alcoholic fatty liver disease (NAFLD). NAFLD is characterized by abnormal hepatic accumulation of triglycerides and other lipids. It has become a worldwide health problem that accelerates cirrhosis, type 2 diabetes mellitus (T2DM), and especially premature cardiovascular morbidity and mortality.

The plasma level of glutathione (GSH) is typically depleted in individuals with metabolism related disorders. However, cellular GSH levels cannot be increased by supplementing GSH and it must be synthesized within the liver either de novo or by salvation pathway. The level of GSH is not enough to maintain and regulate the thiol redox status of the liver in subjects with high hepatic steatosis at fasting stage due to the depletion of glycine. Glycine can be synthesized via the interconversion of serine. It has been shown that the serine synthesis is downregulated in patients with NAFLD and supplementation of serine has attenuated alcoholic fatty liver by enhancing homocysteine metabolism in mice and rats. Depleted liver glutathione is also restored by the administration of N-acetylcystein as in acetaminophen poising. L-carnitine and nicotinamide that both stimulate the transfer of fatty acids from cytosol to mitochondria have been identified as two additional cofactors that are depleted in patients with NAFLD.

In this study, the kinetics in blood of pivotal metabolic cofactors, serine, L-carnitine, N-acetylcystein and nicotinamide after single and simultaneous dietary supplementation, are measured.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Dietary supplement: Cofactors

Detailed Description

In 10 healthy subjects with BMI <30 kg/m2 the plasma concentrations of 4 natural compounds (nicotinamide riboside, L-carnitine, L-serine and N-acetylcystein) are measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLCMSMS) after individual and combined administration, on five consecutive days and at every hour during 9 hours after administration. The study will start at 8:00 every morning and at each time point, blood samples will be collected.

The taste and any potential sensing of the co-factors such as vertigo, nausea, bowel movement will be recorded.

Each participant will receive one oral dose of Day 1: 1 g nicotinamide riboside; Day 2: 3 g L-carnitine; Day 3: 5 g N-acetylcystein; Day 4: 20 g L-serine; Day 5: combined 1 g nicotinamide riboside, 3 g L-carnitine, 5 g N-acetylcystein, and 20 g L-serine

In addition, untargeted metabolomics analysis as well as O-link proteomics analysis we be performed to study effect of the administered cofactors.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Göteborg, Sweden, 411 31
    • Hanns-Ulrich Marschall
  • Göteborg, Sweden
    • Sahlgrenska Academy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

Healthy without any medication, no smokers, no obesity

Exclusion Criteria:

Any known disease, obesity

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intervention; Oral administration of cofactors, 1g nicotinamide riboside, 3g L-carnitine, 20g serine and 5g N-acetylcystein, first as single compounds, then combined, on 5 days	Dietary supplement: Cofactors; Oral administration of 1g nicotinamide riboside, 3g L-carnitine, 20g serine and 5g N-acetylcystein, first as single compounds, then combined, on 5 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of plasma levels of nicotinamide riboside measured by mass spectrometry	Plasma levels of nicotinamide riboside by UPLCMSMS at 8 time points during 24h after administration	Twenty-four hours after administration
Changes of plasma levels of L-carnitine measured by mass spectrometry	Plasma levels of L-carnitine (nM) measured by UPLCMSMS at 8 time points during 24h after administration	Twenty-four hours after administration
Changes of plasma levels of L-serine measured by mass spectrometry	Plasma levels of L-serine (nM) measured by UPLCMSMS at 8 times points during 24h after administration	Twenty-four hours after administration
Changes of plasma levels of N-acetylcystein measured by mass spectrometry	Plasma levels of N-acetylcystein (nM) measured by UPLCMSMS at 8 times points during 24h after administration	Twenty-four hours after administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the plasma level of metabolites associated with the supplementation of metabolic co-factors.	Untargeted metabolomic analysis using mass spectrometry. (Untargeted = not pre-specified in terms of outcome)	Twenty-four hours after administration of combined cofactors
Changes in the plasma level of inflammation-related proteins associated with the supplementation of metabolic co-factors.	Changes in the plasma level of inflammation related proteins associated with the supplementation of metabolic co-factors.	Twenty-four hours after administration of combined cofactors

Collaborators and Investigators

• Sponsor: Sahlgrenska University Hospital, Sweden
• Collaborators: Karolinska Institutet; Chalmers University of Technology
• Investigators: Principal Investigator: Hanns-Ulrich Marschall, Prof, Sahlgrenska University Hospital, Sweden

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2018
• Primary Completion (ACTUAL): November 1, 2018
• Study Completion (ACTUAL): December 1, 2018

Study Registration Dates

• First Submitted: February 4, 2019
• First Submitted That Met QC Criteria: February 11, 2019
• First Posted (ACTUAL): February 12, 2019

Study Record Updates

• Last Update Posted (ACTUAL): February 15, 2019
• Last Update Submitted That Met QC Criteria: February 12, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: L-carnitine; N-acetylcystein; nicotinamid riboside; L-serine
• Other Study ID Numbers: Cofactor Calibration 1.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No