The major OBJECTIVES in this application are to understand the mechanisms and pathways by which impaired hepatic VLDL secretion promotes fibrosis and HCC. Our proposal is SIGNIFICANT because of the unmet need for a more nuanced approach to identify subsets of NAFLD where a more tailored approach might inform strategies for prevention and reversal of NASH/fibrosis and HCC. The BACKGROUND to this proposal is that genetic defects (APOB, APOC3, MTTP, TM6SF2) that impair hepatic VLDL secretion cause hepatic steatosis and progress to NASH with fibrosis and HCC, even without obesity or insulin resistance. In addition, VLDL secretion is relatively (ie paradoxically) impaired in a subset of insulin-resistant, NAFLD patients. Accordingly our overall SCIENTIFIC PREMISE is that is that elucidating pathways whereby impaired hepatic VLDL secretion promotes fibrosis and HCC will identify novel, druggable pathways for fibrosis reversal and HCC prevention in a metabolic subset of NAFLD/NASH. Our proposal is supported by KEY PRELIMINARY DATA including:
(AIM 1) CDK4 activation as a mediator of fibrogenic injury with impaired hepatic VLDL secretion following liver-specific microsomal triglyceride transfer protein (Mttp) deletion (Mttp-LKO). We also find increased genotoxic HCC in Mttp-LKO mice and will pursue the underlying mechanisms involved.
(AIM 2). We have developed novel tissue-specific Tm6sf2 knockout mice to examine the metabolic and fibrogenic pathways associated with both loss of function and conditional (WT and E167K) rescue, to discern mechanisms of fibrosis and tumorigenesis with impaired VLDL secretion resulting from liver-specific Tm6sf2 deletion, compared to mice with Mttp deletion.
The AIMS of this proposal are:
AIM 1. What pathways and mediators promote fibrosis and HCC with impaired hepatic VLDL secretion and how are these pathways modified by altered lipid droplet (LD) turnover? Aim 1 builds on the findings with CDK4 activation pathways and will identify lipidomic mediators of fibrogenesis as well as examining strategies for modifying LD turnover to mitigate the development of fibrosis and HCC.
AIM 2. How does liver specific Tm6sf2 (Tm6-LKO) deletion, and rescue, alter hepatic lipid homeostasis and how do these adaptations influence hepatic fibrogenic injury and HCC? Aim 2 asks how LD formation, turnover and FA utilization for VLDL secretion is altered in Tm6-LKO mice and with what implications for fibrosis and HCC. We also ask how those pathways differ from those elucidated with Mttp deletion and, further, how AAV8-mediated rescue with either wild-type (E167) or mutant (K167) Tm6sf2 modifies those metabolic phenotypes and with what impact for hepatic fibrogenesis and HCC in Tm6 LKO mice. Taken together, we address a CRITICAL KNOWLEDGE GAP by exploring novel pathways of fibrogenic injury and HCC, focusing on defective VLDL secretion as a nexus point directly relevant to a subset of genetic and acquired etiologies of NAFLD/NASH.

Public Health Relevance

Nonalcoholic Fatty Liver Disease (NAFLD) progresses in a significant subset of patients to NASH with fibrosis and liver cancer, for reasons that are almost completely unknown and for which there is no proven treatment. We will address key pathways for fibrosis and cancer development in a subset of NAFLD characterized by the inability of the liver to export fat. Our mouse models will allow us to identify novel targets to prevent fibrosis and liver cancer in a representative genetic subset of NAFLD patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK119437-01A1
Application #
9825279
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Burgess-Beusse, Bonnie L
Project Start
2019-07-16
Project End
2023-04-30
Budget Start
2019-07-16
Budget End
2020-04-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130