Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in α-1-antitrypsin deficiency

Abstract

ReviewAutophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in a-1-antitrypsin deficiency DH Perlmutter a-1-Antitrypsin (AT) deficiency is a relatively common autosomal co-dominant disorder, which causes chronic lung and liver disease. A point mutation renders aggregation-prone properties on a hepatic secretory protein in such a way that the mutant protein is retained in the endoplasmic reticulum of hepatocytes rather than secreted into the blood and body fluids where it ordinarily functions as an inhibitor of neutrophil proteases. A loss-of-function mechanism allows neutrophil proteases to degrade the connective tissue matrix of the lung causing chronic emphysema. Accumulation of aggregated mutant AT in the endoplasmic reticulum of hepatocytes causes liver inflammation and carcinogenesis by a gain-of-toxic function mechanism. However, genetic epidemiology studies indicate that many, if not the majority of, affected homozygotes are protected from liver disease by unlinked genetic and/or environmental modifiers. Studies performed over the last several years have demonstrated the importance of autophagy in disposal of mutant, aggregated AT and raise the possibility that predisposition to, or protection from, liver injury and carcinogenesis is determined by the balance of de novo biogenesis of the mutant AT molecule and its autophagic disposal.

Molecular characterization of the new defective Pbresciaalpha1-antitrypsin allele

“…Moreover, even if it is known that α 1 AT accumulation appears as massive deposit in PI*Z/Z individuals, only a susceptible subgroup (10-15%) develops severe liver disease. Indeed, it is well known that either genetic or environmental modifiers may contribute to the variable severity of liver disease associated to the Z allele (DeMeo and Silverman, 2004;Greene, et al, 2008;Perlmutter, 2009). This may be similar for P brescia allele and warrants further investigation.…”

ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

“…Studies performed in cultured mammalian cells responding to a variety of insults eventually leading to cell death, support the view that autophagy stimulation in dying cells represents an attempt to alleviate the stress rather than amplifying it. 44 Thus blockage of autophagy by means of RNAi-mediated knockdown of essential autophagy genes interferes with the clearance of toxic aggregateprone proteins in neuronal cells, 40,45 hepatocytes, 46 and in a variety of physiopathological conditions linked to ER stress, 47 ultimately resulting in an enhancement of cell death. Studies focusing on the role of autophagy in cancer propagation and in response to therapy, which is the focus of paragraph Autophagy, ROS and cancer: A two-faced story, also define autophagy stimulation as a crucial adaptation mechanism in the face of chronic metabolic stress during carcinogenesis or acute cellular injury in response to a variety of therapeutic drugs.…”

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

“…Autophagy forms an important pathway for mobilization of misfolded mutant protein aggregates. 64 Although the exact mechanism of liver injury in alpha 1 AT deficiency is unknown, increase in autophagy induction by carbamazepine has been tested to mobilize the protein aggregates and decrease hepatic fibrosis. Carbamazepine has been shown to reduce these inclusions in mouse models by induction of autophagy along with reduced liver injury and fibrosis.…”