Bile Duct Ligation Induces ATZ Globule Clearance in a Mouse Model of α-1 Antitrypsin Deficiency

Abstract

Background Alpha-1 antitrypsin deficiency (A1ATD) can progress to cirrhosis and hepatocellular carcinoma; however, not all patients are susceptible to severe liver disease. In A1ATD, a toxic gain-of-function mutation generates insoluble ATZ “globules” in hepatocytes, overwhelming protein clearance mechanisms. The relationship between bile acids and hepatocytic autophagy is less clear, but may involve altered gene expression pathways. Based on previous findings that bile duct ligation (BDL) induces autophagy, we hypothesized that retained bile acids may have hepatoprotective effects in PiZZ transgenic mice, which model A1ATD. Methods We performed BDL and partial BDL (pBDL) in PiZZ mice, followed by analysis of liver tissues. Results PiZZ liver subjected to BDL showed up to 50% clearance of ATZ globules, with increased expression of autophagy proteins. Analysis of transcription factors revealed significant changes. Surprisingly nuclear TFEB, a master regulator of autophagy, remained unchanged. pBDL confirmed that ATZ globule clearance was induced by localized stimuli rather than diet or systemic effects. Several genes involved in bile metabolism were over-expressed in globule-devoid hepatocytes, compared to globule-containing cells. Conclusions Retained bile acids led to a dramatic reduction of ATZ globules, with enhanced hepatocyte regeneration and autophagy. These findings support investigation of synthetic bile acids as potential autophagy-enhancing agents.

Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Approaches and Future Directions

“…Similarly, cultured human HepG2 cells pre-conditioned with sub-toxic concentrations of the hydrophobic bile acid glycochendeoxycholic acid (GCDCA) adapted towards further insult from GCDCA-induced apoptosis (a process called “hormesis”) [ 62 ]. Khan et al recently demonstrated that BDL accelerated clearance of ATZ globules in PiZ mice, with enhanced autophagy and proliferation of globule-devoid hepatocytes compared to globule-containing cells [ 63 ]. Comparable findings were also confirmed using a partial BDL model, in which the unligated right lobe served as an internal control for the ligated left lobe, supporting localized effects of retained bile acids in PiZ mouse liver [ 63 ].…”

“…Khan et al recently demonstrated that BDL accelerated clearance of ATZ globules in PiZ mice, with enhanced autophagy and proliferation of globule-devoid hepatocytes compared to globule-containing cells [ 63 ]. Comparable findings were also confirmed using a partial BDL model, in which the unligated right lobe served as an internal control for the ligated left lobe, supporting localized effects of retained bile acids in PiZ mouse liver [ 63 ]. These findings suggest a role for bile acid signaling as a potential therapeutic target in A1ATD.…”

Biliary bile acids in hepatobiliary injury – What is the link?

“…The importance of impaired autophagy for pathogenesis of cholestatic liver diseases is under investigation and discussion. 121,122 Several autophagy genes are regulated in an FXR-dependent manner by BAs. 123 Morphological markers for autophagy, such as LC3, p62, LAMP-1, p16, and p21, were found to be induced in PBC livers.…”

Partial Bile Duct Ligation in the Mouse: A Controlled Model of Localized Obstructive Cholestasis

“…More recently, pBDL has been redefined to study liver parenchymal effects of retained bile 10 . By using the same animal for internal control (unligated "sham") and experimental groups, pBDL effectively halves the number of animals needed per experiment, which in turn is more costeffective.…”