De Novo Lipogenesis in Severity of NAFLD

Contribution of De Novo Lipogenesis in Severity of Nonalcoholic Fatty Liver Disease

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.

Study Overview

• Status: Completed
• Conditions: Obesity, Morbid; Bariatric Surgery Candidate; Nonalcoholic Fatty Liver Disease; Nonalcoholic Steatohepatitis

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 Type: Observational
• Enrollment (Actual): 49

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 22 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
De novo lipogenesis	DNL will be measured directly in the liver biopsies	Dec 2019

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Histological scores (NAFLD activity score)	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.	Dec 2019
Liver enzymes	AST and ALT will be measured on the day when liver biopsy is collected	Dec 2019
FibroScan	Liver fat and fibrosis will also be measured non-invasively via FibroScan TM	Dec 2019

Collaborators and Investigators

• Sponsor: University of Missouri-Columbia
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); American Society for Nutrition
• Investigators: Principal Investigator: Elizabeth J Parks, PhD, University of Missouri-Columbia

Publications and helpful links

General 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. doi: 10.1172/JCI23621.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2019
• Primary Completion (Actual): August 21, 2019
• Study Completion (Actual): July 31, 2020

Study Registration Dates

• First Submitted: September 20, 2018
• First Submitted That Met QC Criteria: September 21, 2018
• First Posted (Actual): September 25, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 16, 2024
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Digestive System Diseases; Overweight; Obesity; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Obesity, Morbid
• Other Study ID Numbers: 2012544; R01DK113701 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No