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Intestinally restricted LXR agonism in ameliorating liver failure in short gut syndrome

Award Number: R01DK119147
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: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Intestinally restricted LXR agonism in ameliorating liver failure in short gut syndrome - ABSTRACT Short gut syndrome (SGS) results from surgery that removes a significant length of small intestine in response to different conditions, like necrotizing enterocolitis. In children, the mortality associated with SGS is ~25%, making it one of the most lethal conditions in infancy and childhood. After surgery, remodeling of the remaining bowel segment can facilitate absorptive function and survival. Nonetheless, some patients require long-term parenteral nutrition. Beyond loss of absorptive capacity, a significant complication in SGS patients that survive bowel resection is intestinal failure-associated liver disease (IFALD), regardless of whether patients receive nutrition enterally or parenterally. Clinically, therapies designed to target IFALD after SGS remain elusive. In the first round of funding of this continuation application, The Warner and Randolph lab have shown in mouse models of small bowel resection that gut-derived LPS transiting to the liver from the portal vein initiatesTLR4 signaling in liver macrophages that ultimately drives onset of fibrosis. A significant break on LPS-TLR4 interaction occurred by the binding and neutralization of gut-derived LPS to portal vein high density lipoprotein (HDL). HDL is synthesized in the liver and is also generated by enterocytes in the mice or human ileum, where it depends on expression of the polypeptide apoA1 and the lipid transporter ABCA1 that donates the first lipids to the nascent HDL particle. Loss of enterocyte ABCA1 greatly reduced portal vein HDL, allowing for enhanced LPS activity to reach the liver and exacerbate liver injury after small bowel resection. Conversely, when we increased intestinal HDL by giving the liver X receptor (LXR) agonist GW9365 orally at a low dose to trigger HDL production in the intestine but avoid direct LXR agonism of the liver, the drug was effective in reducing the onset of liver fibrosis in a manner that was dependent upon enterocyte-derived ABCA1. These findings raise the concept that intestinal epithelial activation of the transcription factor LXR may provide therapeutic benefit toward treating IFALD. This grant is designed to consider this concept with the intent to further define the role of LXR and HDL in protecting the liver in SGS models and to move in a translational direction that may support later clinical development of a therapeutic to treat IFALD. We will study how LXR agonism protects the liver in a mouse model of SGS using a novel orally restricted LXR agonist compound WUSTL0717 synthesized by Principal Investigator Elgendy. Pharmacokinetic analysis in mice reveals that WUSTL0717 is indeed restricted to the intestine. To further consider the translational potential of WUSTL0717, Principal Investigator Ajay Jain will provide expertise in SGS studied in piglets. One major advantage of incorporating a piglet model into studies of SGS is that piglets can be provided parenteral nutrition like humans and thus model aspects of the disease not easily studied in mice. Dr. Jain has shown that parenteral nutrition in piglets leads to bacterial overgrowth in the small bowel, resulting in increased LPS translocation to the liver and thereby recapitulating the scenario and possible mechanisms described above in mice.


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 = $590,587 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	7/10/2025	NON-COMPETING CONTINUATION	$590,587
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	2/25/2025	COMPETING CONTINUATION	$15,962
2025	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/25/2025	NON-COMPETING CONTINUATION	-$15,962
														Subtotal = $590,587

Issue Date FY: 2024 ( Subtotal = $604,462 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	4/24/2024	COMPETING CONTINUATION	$604,462
2024	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $604,462

Issue Date FY: 2023 ( Subtotal = $436,527 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/1/2023	NON-COMPETING CONTINUATION	$436,527
														Subtotal = $436,527

Issue Date FY: 2022 ( Subtotal = $436,527 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/25/2022	NON-COMPETING CONTINUATION	$392,875
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/30/2022	NON-COMPETING CONTINUATION	$43,652
														Subtotal = $436,527

Issue Date FY: 2021 ( Subtotal = $436,527 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/24/2021	NON-COMPETING CONTINUATION	$436,527
														Subtotal = $436,527

Issue Date FY: 2020 ( Subtotal = $436,065 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/11/2020	NON-COMPETING CONTINUATION	$436,065
2020	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/6/2020	NEW	$0
														Subtotal = $436,065

Issue Date FY: 2019 ( Subtotal = $438,294 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/19/2019	NEW	$438,294
														Subtotal = $438,294

Grand Total All Awards = $3,378,989

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Intestinally restricted LXR agonism in ameliorating liver failure in short gut syndrome

Award Number: R01DK119147

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: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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