2. Academic Validation
  3. PIDDosome-SCAP crosstalk controls high-fructose-diet-dependent transition from simple steatosis to steatohepatitis

PIDDosome-SCAP crosstalk controls high-fructose-diet-dependent transition from simple steatosis to steatohepatitis

  • Cell Metab. 2022 Oct 4;34(10):1548-1560.e6. doi: 10.1016/j.cmet.2022.08.005.
Ju Youn Kim 1,  Lily Q Wang 2,  Valentina C Sladky 3,  Tae Gyu Oh 4,  Junlai Liu 2,  Kaitlyn Trinh 2,  Felix Eichin 3,  Michael Downes 4,  Mojgan Hosseini 5,  Etienne D Jacotot 6,  Ronald M Evans 4,  Andreas Villunger 7,  Michael Karin 8
Affiliations

Affiliations

  • 1 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: juk005@health.ucsd.edu.
  • 2 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • 3 Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
  • 4 Gene Expression Laboratory, Salk Institute of Biological Studies, La Jolla, CA 9037, USA.
  • 5 Department of Pathology, University of California San Diego, La Jolla, CA 92037, USA.
  • 6 INSERM U1164 Sorbonne Université, Campus Pierre et Marie Curie, Paris 75005, France; Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10033, USA.
  • 7 Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 8 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: karinoffice@health.ucsd.edu.
PMID: 36041455 DOI: 10.1016/j.cmet.2022.08.005
Abstract

Sterol deficiency triggers SCAP-mediated SREBP activation, whereas hypernutrition together with ER stress activates SREBP1/2 via caspase-2. Whether these pathways interact and how they are selectively activated by different dietary cues are unknown. Here, we reveal regulatory crosstalk between the two pathways that controls the transition from hepatosteatosis to steatohepatitis. Hepatic ER stress elicited by NASH-inducing diets activates IRE1 and induces expression of the PIDDosome subunits caspase-2, RAIDD, and PIDD1, along with INSIG2, an inhibitor of SCAP-dependent SREBP activation. PIDDosome assembly activates caspase-2 and sustains IRE1 activation. PIDDosome ablation or IRE1 inhibition blunt steatohepatitis and diminish INSIG2 expression. Conversely, while inhibiting simple steatosis, SCAP ablation amplifies IRE1 and PIDDosome activation and liver damage in NASH-diet-fed Animals, effects linked to ER disruption and preventable by IRE1 inhibition. Thus, the PIDDosome and SCAP pathways antagonistically modulate nutrient-induced hepatic ER stress to control non-linear transition from simple steatosis to hepatitis, a key step in NASH pathogenesis.

Keywords

ER stress; IRE1; NAFLD; NASH; PIDDosome; SCAP; SREBP; caspase-2; steatohepatitis; steatosis.

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