ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION (ERAD) IN THE LIVER

Recent literature has revolutionized our view on the patho-physiological importance and the underlying molecular mechanism of endoplasmic reticulum (ER)-associated degradation (ERAD) in health and disease. Aside from being a downstream element of ER stress response or the unfolded protein response (UPR), ERAD also plays a direct and vital role in health and disease, in a substrate-specific and largely UPR-independent manner. The Sel1L-Hrd1 complex is the most conserved branch of mammalian endoplasmic reticulum (ER)-associated degradation (ERAD) machinery. Here, we have focused on the role of ERAD in the liver in the context of energy metabolism, bile homeostasis and cancer pathogenesis. In a recent publication, we reported the discovery of a novel mechanism underlying ERAD-mediated regulation of Fgf21 expression during growth and fasting-feeding. Mice with liver-specific deletion of Sel1L exhibit growth retardation with markedly elevated circulating Fgf21, leading to massive alterations in growth and systemic metabolic profile. Mechanistically, we show that the Sel1L-Hrd1 ERAD complex controls Fgf21 transcription by regulating the ubiquitination and turnover (and thus nuclear abundance) of ER-resident transcription factor Crebh. This study not only establishes the importance of hepatic Sel1L-Hrd1 ERAD in the regulation of systemic energy metabolism, but also reveals a novel hepatic “ERAD-Crebh-Fgf21” axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation. In another study, our data revealed the importance of ERAD in the regulation of bile metabolism, where a deficiency in hepatic ERAD causes significantly impaired secretion of bile acids, cholesterol and phosphatidylcholine into bile, leading to hypercholanemia and extreme sensitivity to dietary bile acid challenge. This occurs due to defective maturation of exporter proteins associated with bile production, owing to faulty ERAD of these proteins. Finally, in a parallel study, we identify and characterize a novel and significant relationship between hepatic ERAD and liver cancer pathogenesis via the Wnt signalling pathway. Here we demonstrate that Sel1L-Hrd1 ERAD in the liver functions to triage the secreted protein Wnt5A during its maturation in the ER. In the absence of ERAD, Wnt5A aggregates and allows unrestrained proliferation of hepatocytes, thereby markedly increasing the propensity to liver cancer development. Taken together, we propose the new concept of “constitutive” or “basal” ERAD and its significance in managing cellular and organismal function, and define novel paradigms underlying ERAD function in both quality and quantity control of proteins synthesized in the ER, and nuclear gene transcription