De Novo Lipogenesis in Severity of NAFLD

• ClinicalTrials.gov Identifier: NCT03683589
• Recruitment Status: Completed
• First Posted: September 25, 2018
• Last Update Posted: October 30, 2020
• Sponsor: University of Missouri-Columbia
• Collaborators: American Society for Nutrition; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Majid Mufaqam Syed Abdul, University of Missouri-Columbia

Study Description

Brief Summary:

NAFLD is the most prevalent liver disease in the U.S., and there is a serious need to understand its progression to the advanced state, nonalcoholic steatohepatitis (NASH). Previous studies has shown that elevated de novo lipogenesis (DNL) is the unique, early event distinguishing patients with NAFLD from equally-obese subjects with low IHTG. The purpose of this study is to directly by measure DNL in human liver tissue and comparing it to liver histological scores from patient biopsies.

Condition or disease
Nonalcoholic Fatty Liver Disease; Nonalcoholic Steatohepatitis; Bariatric Surgery Candidate; Obesity, Morbid

Detailed Description:

The development of nonalcoholic fatty liver disease (NAFLD) progresses from a state of elevated intrahepatic triglycerides (IHTG) to liver inflammation, and ultimately, hepatic apoptosis and fibrosis. NAFLD is the most prevalent liver disease in the U.S., and there is a serious need to understand its progression to the advanced state, nonalcoholic steatohepatitis (NASH). Elevated de novo lipogenesis (DNL) is the unique, early event distinguishing patients with NAFLD from equally-obese participants with low IHTG. DNL is the process of liver synthesis of fatty acids (FAs) from carbohydrate. In humans, studies have shown that DNL significantly predicts the magnitude of IHTG, however, it is unknown whether the pathway plays a role in disease progression. Evidence supporting this concept includes the fact that the primary product of DNL is the saturated FA, palmitate, which in cell culture has been shown to significantly contribute to oxidative stress and inflammation. Recent rodent data show that upregulation of DNL through dietary supplementation of sucrose exacerbated the hepatotoxic effects of excess dietary FAs. A preliminary abstract presented by others at the 2017 Liver Meeting suggested that DNL may not be different between patients with low and high liver fibrosis, although these data were collected using an indirect measure of liver disease. Here, in the present study, the hypothesis will be tested directly by measuring DNL in human liver tissue and comparing it to liver histological scores (NAFLD Activity Score, NAS) from patient samples.

Study Design

• Study Type: Observational
• Actual Enrollment: 49 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Contribution of de Novo Lipogenesis in Severity of Nonalcoholic Fatty Liver Disease
• Actual Study Start Date: February 1, 2019
• Actual Primary Completion Date: August 21, 2019
• Actual Study Completion Date: July 31, 2020

Groups and Cohorts

Group/Cohort
Study group; Participants will receive deuterated water for 10 days before undergoing bariatric surgery. Liver biopsy collected, lipids extracted and DNL measured via GC/MS.

Outcome Measures

Primary Outcome Measures :

1. De novo lipogenesis [ Time Frame: Dec 2019 ]
   DNL will be measured directly in the liver biopsies

Secondary Outcome Measures :

1. Histological scores (NAFLD activity score) [ Time Frame: Dec 2019 ]
   Tissue histology will be performed to obtain NAFLD activity score (NAS). A pathologist, trained in determining the NAS of histological samples, grades them for the quantity of fat present, and the levels of inflammation and fibrosis. A score of 0 is considered completely healthy (devoid of any of these three characteristics), while a score of 8 indicates severe pathology, advanced as far as cirrhosis.
2. Liver enzymes [ Time Frame: Dec 2019 ]
   AST and ALT will be measured on the day when liver biopsy is collected
3. FibroScan [ Time Frame: Dec 2019 ]
   Liver fat and fibrosis will also be measured non-invasively via FibroScan TM

Biospecimen Retention:   Samples Without DNA

Plasma samples will be stored in a -80C freezer. Liver samples will be tested immediately and will not be stored.

Eligibility Criteria

• Ages Eligible for Study: 22 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Sampling Method: Non-Probability Sample

Study Population

The study includes both obese men and women who are undergoing bariatric surgery

Criteria

Inclusion and exclusion criteria are similar to the criteria set by a larger project (NCT03151798).

Inclusion criteria:

• Men and women (pre and post-menopausal)
• Overweight/obese with BMI ≥ 25.9 or ≤ 50.0 kg/m2
• Characteristics of the metabolic syndrome, pre-diabetes (fasting glucose 100-125 mg/dL or 2h glucose 140-200 mg/dL) or diabetes type II
• 22-65 years of age
• use of tobacco products or no use of these products
• Sedentary, ≤ 60 minutes per week of structured physical activity

Exclusion criteria:

• The following conditions exclude subjects for this project because bariatric surgery would not be performed in these populations. Individuals with acute disease or advanced cardiac, liver, or renal disease, excessive alcohol use, anticoagulation therapy, or any severe co-morbid condition limiting life expectancy < 1 year. Women pregnant or trying to become pregnant.

Contacts and Locations

Locations

United States, Missouri

University of Missouri

Columbia, Missouri, United States, 65212

Sponsors and Collaborators

University of Missouri-Columbia

American Society for Nutrition

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Elizabeth J Parks, PhD; University of Missouri-Columbia

More Information

Publications:

Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014 Mar;146(3):726-35. doi: 10.1053/j.gastro.2013.11.049. Epub 2013 Dec 4.

Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005 May;115(5):1343-51.

• Responsible Party: Majid Mufaqam Syed Abdul, Doctoral Candidate, University of Missouri-Columbia
• ClinicalTrials.gov Identifier: NCT03683589
• Other Study ID Numbers: 2012544; R01DK113701 ( U.S. NIH Grant/Contract )
• First Posted: September 25, 2018
• Last Update Posted: October 30, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Digestive System Diseases; Obesity; Overnutrition; Nutrition Disorders; Overweight; Body Weight