No medications are currently available for treatment of nonalcoholic fatty liver disease (NAFLD), an increasingly prevalent disease afflicting about 25% of US adults. NAFLD is caused by excessive fat deposition in the liver (steatosis); can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, hepatocellular carcinoma, liver transplantation, and increased liver-related and all-cause mortality. We have preliminary data that (1) insulin resistance is the strongest modifiable risk factor for developing NAFLD, and (2) individuals genetically predisposed to NAFLD by carrying PNPLA3 rs738409-GG show about a two-fold increased risk of developing NAFLD and a six-fold risk of nonalcoholic steatohepatitis (NASH) when combined with insulin resistance. Despite being at high risk of liver disease, rs738409-GG individuals with insulin resistance are not being especially targeted to help them improve their insulin sensitivity and thus likely improve their NAFLD outcomes. The PI and others have shown that very low-carbohydrate diets (VLCD) are more effective at reducing insulin resistance than many other types of diets, in addition to being effective for weight loss, lowering overall inflammation, and reducing intrahepatic lipid content. We hypothesize that a very low- carbohydrate diet and behavioral support program may be able to achieve NAFLD reversal in adults with steatosis and/or mild fibrosis, especially in a high-risk subpopulation, rs738409-GG individuals. To prepare to test this we will conduct a preliminary exploration of the needs and preferences of individuals with NAFLD for a VLCD program. Then we will adapt our materials based on this feedback. Finally, we will conduct a pilot feasibility and acceptability trial of a 4-month VLCD program in 30 PNPLA3 rs738409 GG adults with NAFLD. This R03 builds off of the PI?s current K01 with NIDDK, which is optimizing a 12-month VLCD program with adults with type 2 diabetes. We anticipate that the research stemming from this grant will lead to future R-level grants at the National Institute of Diabetes and Digestive and Kidney Diseases, as it will provide support for a multicenter randomized controlled trial.

Public Health Relevance

Creating evidence-based interventions for individuals with non-alcoholic fatty liver disease is fundamental to the management of this common disease. Information gained from this study could facilitate the formulation of effective, widely accessible treatments for non-alcoholic fatty liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK124741-01
Application #
9956416
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Spain, Lisa M
Project Start
2020-03-01
Project End
2022-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Nursing
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109