# Control of Lipogenesis and Hepatic Steatosis by Caspase-2

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $416,402

## Abstract

PROJECT SUMMARY
 Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder whose US incidence exceeds
30%. While NAFLD manifests as benign steatosis, in about 15-20% of patients it assumes a much more
aggressive form – non-alcoholic steatohepatitis (NASH). The switch from benign simple steatosis to NASH is
poorly understood, but was suggested to depend on ER stress. Indeed, by feeding MUP-uPA mice, which are
prone to liver ER stress caused by hepatocyte-specific urokinase plasminogen activator (uPA) expression, a
high-fat diet (HFD) we established a faithful model of NASH that readily progresses to hepatocellular carcinoma
(HCC). HFD-fed MUP-uPA mice show ER-stress-dependent and persistent activation of sterol response element
binding proteins (SREBP) 1 and 2, which control de novo lipogenesis (DNL) and cholesterol biosynthesis.
Notably, SREBP1 and 2 remain activated in the MUP-uPA liver without any sign of feedback inhibition, which
shuts down their activity in lipid-loaded cells. DNL is also chronically elevated in NAFLD and hepatic
accumulation of free cholesterol was suggested to convert simple steatosis to NASH. Investigating how liver ER
stress causes persistent SREBP activation, we uncovered a previously unknown pathway in which caspase-2
(Casp2), whose expression is ER-stress-inducible, leads to constitutive activation of site 1 protease (S1P),
thereby initiating SCAP-independent SREBP cleavage in the ER. Casp2-mediated cleavage and activation of
S1P seems to occur in NASH patients and genetic ablation or pharmacological inhibition of Casp2 in MUP-uPA
mice blocks hepatic steatosis and NASH development. To fully establish the mechanistic aspects of this pathway
and its role in hepatic steatosis, we will investigate whether it functions in liver-specific SCAP knockout mice and
determine whether liver-specific Casp2 ablation affects peripheral adiposity and improves energy expenditure in
addition to preventing HFD-induced hepatic steatosis and its progression to NASH. We will also generate knockin
mice that express a Casp2-resistant (C2R) form of S1P and determine whether they are protected from ER-
stress induced hepatic steatosis and adipose tissue expansion. As ER-stress-mediated Casp2 activation and
S1P cleavage seem to depend on Tp53 activity, which results in induction of the Casp2 activator PIDD, we will
examine the role of Tp53 and PIDD in Casp2-dependent S1P cleavage, SREBP1/2 activation, and hepatic
steatosis, thereby establishing a key metabolic function for Tp53 outside of cancer. Finally, we will examine the
hypothesis that the original function of the Casp2-dependent S1P-SREBP activation pathway was to promote
energy storage in the form of liver fat during periods of hypernutrition in preparation for long-term starvation.
While clarifying the role of Casp2-mediated SREBP activation in hepatic steatosis and NASH, these studies will
shed new light on the poorly understood phenomenon of selective insulin resistance,...

## Key facts

- **NIH application ID:** 9886239
- **Project number:** 5R01DK120714-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Michael Karin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,402
- **Award type:** 5
- **Project period:** 2019-03-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886239

## Citation

> US National Institutes of Health, RePORTER application 9886239, Control of Lipogenesis and Hepatic Steatosis by Caspase-2 (5R01DK120714-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9886239. Licensed CC0.

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