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Impaired VLDL secretion in progression of NAFLD and NASH in mice and humans

Award Number: R01DK119437
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/16/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Impaired VLDL secretion in progression of NAFLD and NASH in mice and humans - PROJECT SUMMARY/ABSTRACT The major OBJECTIVES in this application are to expand understanding of mediators of fibrogenic injury and HCC development associated with impaired VLDL secretion in both mice and humans. Our proposal is SIGNIFICANT because of the unmet need to identify subsets of patients with NAFLD whose disease will progress and where a more tailored approach might inform therapeutic strategies for prevention and reversal of NASH/fibrosis and the development of HCC. The BACKGROUND is that genetic defects (APOB, 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 identifying shared pathways in genetically modified mouse models and in metabolic subset of patients with NASH and impaired hepatic VLDL secretion will identify druggable targets for fibrosis reversal and prevention of HCC. Our proposal is supported by KEY PRELIMINARY DATA including: (AIM 1) Liver-specific Tm6sf2 knockout mice (Tm6-LKO), phenocopies the loss-of-function human TM6SF2 (E167K) variant rs58542926 with defective VLDL secretion, hepatic steatosis, fibrosis and increased HCC. We generated Tm6sf2 variant knockin (K167K) mice to examine hepatic VLDL and intestinal chylomicron secretion. We generated variant knockin HepG2 cells and iPS-derived hepatocyte-like cell lines to study the loss-of-function variant in human VLDL assembly. (AIM 2). Liver-specific microsomal triglyceride transfer protein knockout mice (Mttp-LKO) mice crossed into Fabp1–/– mice (ML-DKO) mice exhibit reduced steatosis and decreased fibrosis, yet paradoxically increased HCC. By contrast Mttp-LKO mice crossed into liver-specific DGAT2 knockout mice are protected against HCC. We identified a metabolomic signature in patients with NAFLD/NASH that aligns with impaired VLDL secretion and will examine patients with NASH-HCC. The AIMS of this proposal are: AIM 1. How does how the Tm6sf2 variant alter APOB lipidation and regulate hepatic and intestinal VLDL/chylomicron assembly and secretion? How does the K167K variant influence the development of fibrosis and HCC? How are these pathways in mouse VLDL assembly and secretion replicated in representative human hepatocyte-like cell lines (HepG2, iPS-derived hepatocyte-like cells)? AIM 2. How do modifiers of DNL and LD turnover modify signaling pathways in mice with impaired VLDL secretion (Mttp-LKO) that either promote (Fabp1-dependent) or mitigate (Dgat2-dependent) HCC development? We will examine how pathways identified in mice with impaired VLDL secretion and either increased or decreased HCC susceptibility align with transcriptomic signatures in liver of patients with NASH-HCC and a metabotype of impaired VLDL secretion. 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	3/27/2025	COMPETING CONTINUATION	$1,641
2025	2022	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/27/2025	NON-COMPETING CONTINUATION	-$1,641
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $568,310 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/12/2024	COMPETING CONTINUATION	$568,310
														Subtotal = $568,310

Issue Date FY: 2022 ( Subtotal = $522,202 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/26/2022	NON-COMPETING CONTINUATION	$522,202
														Subtotal = $522,202

Issue Date FY: 2021 ( Subtotal = $522,202 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/22/2021	NON-COMPETING CONTINUATION	$522,202
														Subtotal = $522,202

Issue Date FY: 2020 ( Subtotal = $526,123 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/28/2020	NON-COMPETING CONTINUATION	$526,123
														Subtotal = $526,123

Issue Date FY: 2019 ( Subtotal = $530,966 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/15/2019	NEW	$530,966
														Subtotal = $530,966

Grand Total All Awards = $2,669,803

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Impaired VLDL secretion in progression of NAFLD and NASH in mice and humans

Award Number: R01DK119437

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/16/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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