PIDDosome-SCAP crosstalk controls high-fructosediet-dependent transition from simple steatosis tosteatohepatitis
Kim et al. Cell Metabolism 34, 1–13, October 4, 2022 ª 2022 Elsevier Inc (Impact Factor 27.7)
Kim et al. show that while diets rich in glucose lead to insulin-dependent SREBP activation via the SCAP pathway, diets rich in the saturated fatty acids (FAs) and fructose trigger ER stress and INSIG2 induction, which inhibits SCAP-dependent SREBP activation. Instead, ER stress results in Casp2/PIDDosome dependent SREBP activation
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
Ylva Carlsson, MD,1,2 Leslie Schwendimann, BS,3,4 Regina Vontell, MA, HTL (ASCP),5 Catherine I. Rousset, PhD,1,5 Xiaoyang Wang, MD, PhD,1 Sophie Lebon, Ing.,3,4 Christiane Charriaut-Marlangue, PhD,3,4 Veena Supramaniam, MD,6 Henrik Hagberg, MD, PhD,1,2,5, Pierre Gressens, MD, PhD,3,4,5 and Etienne Jacotot, PhD1,3,4,5
From the 1 Perinatal Center, Department of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; 2 Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg, Sweden; 3 INSERM, U676, Paris, France; 4 Denis Diderot Faculty of Medicine, University Paris Diderot, Sorbonne Paris Cite, UMR676, Paris, France; 5 Perinatal Brain Injury Group, Centre for the Developing Brain, Department of Reproductive Biology, Institute of Reproductive and Developmental Biology, Imperial College, London, United Kingdom; and 6 Perinatal Imaging Group, Centre for the Developing Brain, Robert Steiner Magnetic Resonance Unit, Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, United Kingdom.
ANN NEUROL 2011;00:000–000