ER Stress in NAFLD

October 22, 2013 updated by: Charles R. Flynn, Vanderbilt University

Phospholipid Endoplasmic Reticulum Stress in Nonalcoholic Fatty Liver Disease

The investigators overall hypothesis is that exacerbation of endoplasmic reticulum (ER) stress in the liver is associated with significant alterations in phosphatidylcholines that drive the NASH phenotype in obese humans. The investigators plan to examine this hypothesis in a well-characterized cohort of obese subjects that are scheduled for bariatric surgery. Methyl-D9-choline chloride will be infused before and after a 2-week high fructose or glucose feeding to determine the biosynthesis and kinetics of secretory lipoprotein phospholipids. It is proposed that phospholipid metabolism play an important role in the pathogenesis or etiology of fatty liver in non-alcoholic conditions through mechanisms that invoke ER and oxidative stress responses.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Study Type

Interventional

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

30 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Ambulatory females age 30-60 years old
  • Women of all ethnic groups
  • BMI≥35 kg/m2
  • Approval for Roux-en-Y gastric bypass or sleeve gastrectomy.

Exclusion Criteria:

  • Smoking >7 cigarettes per day
  • Previous malabsorptive or restrictive intestinal surgery
  • Pregnant or breastfeeding
  • Recent history of neoplasia (<5 years ago)
  • Malabsorptive syndromes
  • Inflammatory intestinal disease
  • Patients with established organ dysfunction
  • Diagnosis of type 1 or type 2 diabetes mellitus or current use of anti-diabetic medication (last 30 days; last 60days for thiazolidinediones)
  • Diagnosed hyperbetalipoproteinemia or hypobetalipoproteinemia
  • Patients on cholesterol lowering medicines
  • Vegan diet
  • Hepatic fat content <10% by MRI
  • Inability to comply with study protocol such as unable to make study visits or be available daily for phone contact
  • Any condition which would interfere with MRI or PET studies, e.g. claustrophobia, cochlear implant, chronic back pain limiting ability to lay flat, metal fragments in eyes, cardiac pacemaker, neural stimulator, tattoos with iron pigment and metallic body inclusions or other metal implanted in the body which may interfere with MRI scanning.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Fructose
Participants will receive fructose (3g/kg/day) for 2 weeks.
Drug: methyl-D9-choline
Subjects in both arms will be infused with methyl-D9-choline in order to assess the biosynthesis and kinetics of secretory lipoprotein phospholipids.
Active Comparator: Glucose
Participants will receive glucose (3g/kg/day) for 2 weeks.
Drug: methyl-D9-choline
Subjects in both arms will be infused with methyl-D9-choline in order to assess the biosynthesis and kinetics of secretory lipoprotein phospholipids.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Net hepatic phospholipid production
Time Frame: Baseline and 2 weeks
Net hepatic phospholipid production will be determined using [11C]choline dynamic Positron Emission Tomography (PET) before and after high fructose feeding for two weeks. A similar group of control obese subjects will undergo the same procedures before and after two weeks isocaloric glucose feeding.
Baseline and 2 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Kinetics of secretory lipoprotein phospholipids
Time Frame: Baseline and 2 weeks
The biosynthesis and kinetics of secretory lipoprotein phospholipids will be determined using methyl-D9-choline chloride infusion before and after high fructose (or glucose) feeding.
Baseline and 2 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in zonation of phospholipids and PEMT in liver tissues
Time Frame: 60 months
Changes in zonation of phospholipids and PEMT in liver tissues acquired from the same subjects intraoperatively during bariatric surgery will be assessed using MALDI-IMS.
60 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vanderbilt University

Investigators

  • Study Chair: Naji N Abumrad, MD, Vanderbilt University Medical Center
  • Principal Investigator: Charles R Flynn, PhD, Vanderbilt University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2013

Primary Completion (Anticipated)

October 1, 2017

Study Completion (Anticipated)

April 1, 2018

Study Registration Dates

First Submitted

March 5, 2013

First Submitted That Met QC Criteria

March 6, 2013

First Posted (Estimate)

March 8, 2013

Study Record Updates

Last Update Posted (Estimate)

October 23, 2013

Last Update Submitted That Met QC Criteria

October 22, 2013

Last Verified

October 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ER stress

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Obesity

Clinical Trials on methyl-D9-choline

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Equatorial Guinea

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe