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Control of Lipogenesis and Hepatic Steatosis by Caspase-2

Award Number: R01DK120714
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: 03/15/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Control of Lipogenesis and Hepatic Steatosis by Caspase-2 - Project Summary We have established the existence of an endoplasmic reticulum (ER) stress responsive and caspase 2 (Casp2) dependent pathway that leads to activation of sterol regulatory element binding proteins 1 and 2 (SREBP1/2), the master regulators of fatty acid and cholesterol metabolism. The Casp2-dependent pathway operates independently of SREBP cleavage activation protein (SCAP), the major activator of canonical SREBP signaling and the target for its feedback inhibition and negative regulation by sterols and other lipids. SCAP-dependent SREBP signaling is activated when sterol concentrations are low and during hepatic insulin resistance and may account for simple steatosis (NAFL), the benign form of non-alcoholic fatty liver disease (NAFLD). Conversely, the Casp2-dependent pathway is activated during hepatocyte ER stress and leads to non-alcoholic steatohepatitis (NASH), the aggressive form of NAFLD, characterized by liver damage and inflammation, and at advanced stages by loss of liver fat. Importantly, we discovered that the two pathways are engaged in negative crosstalk, such that SCAP-dependent SREBP activation attenuates ER stress, likely via ER membrane expansion, whereas activation of the Casp2-dependent pathway by the ER stress sensor and transducer IRE1 is associated with induction of INSIG2, an inhibitor of SCAP-dependent SREBP activation. Moreover, inhibition of SCAP-dependent SREBP signaling potentiates ER stress, which enhances IRE1 activation, resulting in elevated expression of INSIG2, Casp2 and PIDD1, a component of the PIDDosome complex, which includes Casp2 and the scaffold protein RAIDD. In addition to Casp2 activation, PIDD1 may target the PIDDosome complex to the ER membrane, thereby enabling cleavage of site 1 protease (S1P) by Casp2, the first step in the non-canonical SREBP activation pathway. We postulate that the mutually exclusive interactions between the two pathways contribute to the sharp transition from simple steatosis to NASH. We will test this hypothesis in three specific aims. 1. Test the hypothesis that elevated IRE1 activity, Casp2 activation and inhibition of SCAP- dependent SREBP activation control human NASH progression, using an extensive collection of NAFLD biopsies available at UCSD and a novel human liver spheroid model of NAFLD/NASH. 2. Test the hypothesis that INSIG2 induction inhibits SCAP-dependent SREBP activation and potentiates the Casp2- dependent pathway by enhancing ER stress and IRE1 activation. These studies will be conducted in mouse models and will deploy state-of-the-art high-content spatial transcriptomics. 3. Determine the role of IRE1 and its downstream effectors in NAFL to NASH progression in mouse models and human spheroids, and the suitability of these mediators to therapeutic targeting. Impact: these studies will shed new light on the mechanistic basis for Casp2-dependent SREBP activation and the role of ER stress, IRE1 and its effectors in NASH pathogenesis, laying the foundation to new therapeutic interventions.


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: 2026 ( Subtotal = $48,138 )
2026	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	1/29/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$393,221
2026	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	8	2/11/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$139,522
2026	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	1/29/2026	NON-COMPETING CONTINUATION	-$318,610
2026	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	7	3/26/2026	NON-COMPETING CONTINUATION	$0
2026	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	2/11/2026	NON-COMPETING CONTINUATION	$113,049
														Subtotal = $48,138

Issue Date FY: 2025 ( Subtotal = $546,309 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	6/13/2025	NON-COMPETING CONTINUATION	$546,309
														Subtotal = $546,309

Issue Date FY: 2024 ( Subtotal = $524,457 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	5/9/2024	NON-COMPETING CONTINUATION	$524,457
2024	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	4/10/2024	COMPETING CONTINUATION	$169,575
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/10/2024	NON-COMPETING CONTINUATION	-$169,575
														Subtotal = $524,457

Issue Date FY: 2023 ( Subtotal = $546,309 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/14/2023	COMPETING CONTINUATION	$546,309
2023	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $546,309

Issue Date FY: 2022 ( Subtotal = $417,724 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/8/2021	NON-COMPETING CONTINUATION	$375,950
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/29/2022	NON-COMPETING CONTINUATION	$41,774
														Subtotal = $417,724

Issue Date FY: 2021 ( Subtotal = $417,063 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/1/2021	NON-COMPETING CONTINUATION	$41,709
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/30/2020	NON-COMPETING CONTINUATION	$375,354
														Subtotal = $417,063

Issue Date FY: 2020 ( Subtotal = $416,402 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/10/2020	NON-COMPETING CONTINUATION	$41,642
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/8/2020	NON-COMPETING CONTINUATION	$374,760
														Subtotal = $416,402

Issue Date FY: 2019 ( Subtotal = $415,961 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/5/2019	NEW	$415,961
														Subtotal = $415,961

Grand Total All Awards = $3,332,363

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Control of Lipogenesis and Hepatic Steatosis by Caspase-2

Award Number: R01DK120714

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: 03/15/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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