ER Stress in NAFLD

NCT01807910 | Withdrawn Early Phase 1

• 1 other identifier: ER stress
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Obesity; NAFLD

Keywords

Obesity; NAFLD; NASH; Steatosis

Outcome Measures

Primary Outcomes (1)

• Net hepatic phospholipid production

  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 Outcomes (1)

• Kinetics of secretory lipoprotein phospholipids

  Baseline and 2 weeks

Other Outcomes (1)

• Changes in zonation of phospholipids and PEMT in liver tissues

  60 months

Study Arms (2)

Fructose

EXPERIMENTAL

Participants will receive fructose (3g/kg/day) for 2 weeks.

Drug: methyl-D9-choline

Glucose

ACTIVE COMPARATOR

Participants will receive glucose (3g/kg/day) for 2 weeks.

Drug: methyl-D9-choline

Interventions

methyl-D9-choline DRUG

Subjects in both arms will be infused with methyl-D9-choline in order to assess the biosynthesis and kinetics of secretory lipoprotein phospholipids.

Fructose; Glucose

Eligibility Criteria

• Age: 30 Years - 60 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

MeSH Terms

Conditions

Obesity; Non-alcoholic Fatty Liver Disease; Fatty Liver

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Liver Diseases; Digestive System Diseases

Study Officials

• Charles R Flynn, PhD

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

• Naji N Abumrad, MD

  Vanderbilt University Medical Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: March 5, 2013
• First Posted: March 8, 2013
• Study Start: October 1, 2013
• Primary Completion: October 1, 2017
• Study Completion: April 1, 2018
• Last Updated: October 23, 2013

Record last verified: 2013-10

Locations

US (1)