Clinical trial NCT03683589: De Novo Lipogenesis in Severity of NAFLD
Official title: Contribution of De Novo Lipogenesis in Severity of Nonalcoholic Fatty Liver Disease
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Nonalcoholic Fatty Liver Disease
Nonalcoholic Steatohepatitis
Bariatric Surgery Candidate
Obesity, Morbid
Lead sponsor: University of Missouri-Columbia
Sponsor class: OTHER
Collaborators: name: American Society for Nutrition
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2018-09-25
Enrollment: 49
Sex: ALL
Minimum age (years): 22
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study includes both obese men and women who are undergoing bariatric surgery

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.

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.

Eligibility 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.

Primary outcomes:
measure: De novo lipogenesis
timeFrame: Dec 2019
Secondary outcomes:
measure: Histological scores (NAFLD activity score)
timeFrame: Dec 2019
measure: Liver enzymes
timeFrame: Dec 2019
measure: FibroScan
timeFrame: Dec 2019
Other outcomes:
Locations:
city: Columbia
country: United States
facility: University of Missouri
state: Missouri
Study officials:
affiliation: University of Missouri-Columbia
name: Elizabeth J Parks, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.