NAFLD, Obesity
Conditions
Keywords
Obesity, NAFLD, NASH, Steatosis
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.
Interventions
DRUGmethyl-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.
Sponsors
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
FEMALE
Age
30 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Net hepatic phospholipid production | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kinetics of secretory lipoprotein phospholipids | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in zonation of phospholipids and PEMT in liver tissues | 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. |
Countries
United States
Outcome results
None listed