The PI*Z variant of the alpha-1 antitrypsin (AAT) protein triggers the canonical unfolded protein response, according to a study published in Hepatology Communications. Moreover, hepatocytes survive proapoptotic unfolded protein response by the selective suppression of the unfolded protein response branches.

“Our data improve understanding of underlying pathological molecular mechanisms of PI*Z [AAT deficiency] liver disease,” the authors of the study said.

PI*Z is the most common variant causing AAT deficiency (AATD). It results in glutamine of lysine substitution in position 342 of the amino acid sequence of the AAT protein leading to protein misfolding and accumulation in the endoplasmic reticulum of hepatocytes ultimately resulting in hepatocellular injury, liver fibrosis, and hepatocellular carcinoma.

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The unfolded protein response is a mechanism that normally reduces endoplasmic reticulum stress. However, it is not known whether PI*Z AAT triggers the unfolded protein response in liver cells.

Here, a team of researchers led by Mark L. Brantly, MD, from the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, at the University of Florida in Gainesville used a novel human cell line and a mouse model to investigate this.

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The researchers observed robust activation of the unfolded protein response in the PI*Z AAT hepatocyte cell line compared to a cell line expressing normal ATT. The caspase cascade was also activated in the Z hepatocytes and markers of apoptosis and autophagy, as well as chaperones, were increased.

The unfolded protein response signaling branches were selectively attenuated in the novel PI*Z mouse model. More precisely, the protein kinase R-like endoplasmic reticulum kinase and inositol-requiring enzyme1α branches were suppressed. On the other hand, the activating transcription factor 6α branch stayed active.

“This new insight into the mechanisms by which hepatocytes respond to PI*Z AAT accumulation is beneficial for the development of new therapeutic strategies for AATD,” the researchers concluded.


Lu Y, Wang LR, Lee J, et al. The unfolded protein response to PI*Z alpha-1 antitrypsin in human hepatocellular and murine models. Hepatol Commun. Published online May 27, 2022. doi:10.1002/hep4.1997