ER Stress in NAFLD

Study Overview
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Brief Summary
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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.

Official Title
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Phospholipid Endoplasmic Reticulum Stress in Nonalcoholic Fatty Liver Disease

Conditions
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Obesity, NAFLD

Intervention / Treatment
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* Drug: methyl-D9-choline


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kinetics of secretory lipoprotein phospholipids | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, NAFLD, NASH, Steatosis