Hepatic fibrosis and carcinogenesis in α1-antitrypsin deficiency: a prototype for chronic tissue damage in gain-of-function disorders

Abstract

In α1-antitrypsin (AT) deficiency, a point mutation renders a hepatic secretory glycoprotein prone to misfolding and polymerization. The mutant protein accumulates in the endoplasmic reticulum of liver cells and causes hepatic fibrosis and hepatocellular carcinoma by a gain-of-function mechanism. Genetic and/or environmental modifiers determine whether an affected homozygote is susceptible to hepatic fibrosis/carcinoma. Two types of proteostasis mechanisms for such modifiers have been postulated: variation in the function of intracellular degradative mechanisms and/or variation in the signal transduction pathways that are activated to protect the cell from protein mislocalization and/or aggregation. In recent studies we found that carbamazepine, a drug that has been used safely as an anticonvulsant and mood stabilizer, reduces the hepatic load of mutant AT and hepatic fibrosis in a mouse model by enhancing autophagic disposal of this mutant protein. These results provide evidence that pharmacological manipulation of endogenous proteostasis mechanisms is an appealing strategy for chemoprophylaxis in disorders involving gain-of-function mechanisms.

Figure 1.

Serpin folding and misfolding. (A) Active serpins fold into a metastable state. Binding of target protease results in RCL cleavage. The serpin undergoes a radical conformational change (RCL/s4A incorporation into α-sheet A) that culminates in protease inhibition via distortion of the catalytic residues. (B) Loop-sheet model of serpin polymerization. The RCL of one molecule is inserted into the open α-sheet A of another. (C) Domain-swapped model of serpin polymerization. The model is based on the structure of a domain-swapped AT dimer, where s5A and s4A (RCL) of a donor molecule insert into the α-sheet A of a recipient. (D) Normal serpins may fold through a polymerogenic intermediate that is stabilized by certain mutations. Black dashed arrow indicates gap in α-sheet A that accommodates s5A to form the s4A (RCL) exposed native form in (A) or the s5A and s4A domain-swapped structure in (C). (Reproduced from Whisstock et al. 2010 and printed with permission from the American Society for Biochemistry and Molecular Biology © 2010.)

Figure 2.

Cellular factors that determine whether an AT-deficient individual is protected or susceptible to liver disease. In the susceptible host, there is greater accumulation of insoluble ATZ in the ER because of subtle alterations in putative proteostasis network regulatory mechanisms. Here these proteostasis regulatory mechanisms are envisioned as either ER degradation pathways or cellular protective responses.

Figure 3.

Cellular action of carbamazepine (CBZ). CBZ enhances autophagic disposal of insoluble ATZ (red globules). Soluble ATZ may be secreted (top) or transported by ERAD for degradation by the proteasome.