[초청강연] How Diet regulates NASH progression.  Casp2PIDDosome: A New Regulator of Hepatic Lipid Metabolism

Title: How Diet regulates NASH progression.
Casp2PIDDosome: A New Regulator of Hepatic Lipid Metabolism
Name : Ju Youn Kim
Affiliation: University of California San Diego
Obesity is pandemic, affecting approximately 40% population across the world, and its
associated complications are prevalent. Of these, non-alcoholic fatty liver diseases (NAFLD) is
becoming the most serious liver complication that causes a heavy social burden and demands high
medical costs. Epidemiology indicates that a change in lifestyle and dietary patterns significantly affect
the incidence of obesity. Indeed, consumption of western diet (WD), of which the ingredients contain
a high portion of processed meat, saturated fats, and refined sweeteners, is steeply increasing and
closely correlated with the prevalence of obesity and metabolic syndrome (MS). However, the
pathogenic mechanism linking obesogenic diet to NASH is far from clear.
Sterol regulated element binding protein (SREBP) is the master regulator of hepatic lipid
synthesis: SREBP1c mainly regulates triglyceride synthesis and SREBP2 synthesizes cholesterol.
Sterol deficiency triggers SCAP-mediated SREBP activation, whereas hypernutrition together with
ER-stress activate SREBP1/2 via caspase-2 (Casp2), the most conserved cysteine protease,
promoting lipid synthesis in response to ER stress by leading non-canonical activation and secretion
of site-1 protease (S1P). Hence, we proposed serum S1P as an early detection marker and inhibition
of Casp2 as a therapeutic approach for patients with NASH (Kim et al., Cell 2018). However, whether
these pathways interact and how they are selectively activated by different dietary cues is unknown.
In recent study, 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 (Kim, et al., Cell Metabolism in
revision).