Pioglitazone helps limit liver fibrosis spread in rat cholestasis model
PPAR-gamma activation helped protect regions with preserved bile flow
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In a rat model of segmental cholestasis, a condition in which bile flow is blocked in certain areas of the liver, treatment with pioglitazone helped limit the spread of inflammation and fibrosis-related changes into neighboring liver regions where bile flow was preserved, a study showed.
However, liver regions directly affected by blocked bile flow and already showing scarring, or fibrosis, were largely resistant to treatment, the data showed.
“These findings demonstrate that injury [variability] and partial preservation of bile flow critically determine … therapeutic responsiveness, supporting [PPAR-gamma] activation as a preventive antifibrotic strategy to limit fibro-inflammatory propagation in vulnerable [liver] regions during segmental cholestasis,” the researchers wrote.
An early version of the study, “Residual bile flow shapes PPARγ-mediated antifibrotic responses in experimental segmental cholestasis,” was published in Scientific Reports by a team of researchers in Brazil.
Segmental cholestasis can spread liver damage
Cholestasis occurs when the flow of bile, a digestive fluid produced by the liver, is reduced or blocked, causing bile and related substances to build up in the liver and blood. Too much bile in the liver can cause tissue damage and fibrosis.
Obstructive cholestasis, where bile flow is blocked, is a feature of several liver diseases, including biliary atresia and primary sclerosing cholangitis. In segmental cholestasis, bile flow blockage is restricted to specific areas of the liver, but fibrosis can extend to neighboring liver regions where bile flow is preserved.
“Segmental cholestasis represents a clinically relevant but underexplored condition, particularly in pediatric settings such as post-Kasai biliary atresia and [post-liver transplant] biliary strictures, where fibrosis often progresses despite partial preservation of bile flow,” the researchers wrote.
The Kasai surgery, which aims to restore bile flow, is the first-line treatment for biliary atresia. Biliary strictures are abnormal narrowings of the bile ducts, the tubes that transport bile, that can lead to obstruction.
It’s thought that signaling molecules released from the cholestatic portion of the liver help spread inflammatory and fibrosis-related changes to areas where bile flow is preserved.
A class of drugs called PPAR-gamma agonists, which activate a pathway involved in controlling inflammation and fibrosis, has been studied as a potential approach to reduce inflammation and scarring in several experimental settings.
However, “it remains unclear whether [PPAR-gamma] activation is able to modulate [fibrosis formation] in segmental cholestatic lesions,” the researchers wrote.
Pioglitazone protected less-injured liver region
Here, the scientists investigated whether treatment with a PPAR-gamma agonist called pioglitazone could reduce fibrosis caused by segmental cholestasis and limit the spread of inflammatory and fibrosis-related signals into liver regions with preserved bile flow.
To create a segmental cholestasis model, newly weaned rats underwent selective bile duct ligation, a surgical procedure in which some bile ducts are tied off while others are left intact. Starting three days after surgery, some rats were treated with pioglitazone.
Treatment resulted in a protective effect specific to the non-cholestatic liver region, where bile flow was preserved. In that region, treated rats had a marked reduction in inflammation and liver cell injury relative to untreated animals. No significant improvement in tissue appearance was noted in the cholestatic, or directly affected, liver region with pioglitazone treatment.
In line with these findings, untreated rats showed marked fibrosis in both cholestatic and non-cholestatic liver regions, while pioglitazone-treated animals had less fibrosis only in the non-cholestatic region. These findings indicate “that the protective effects of [PPAR-gamma] activation are spatially restricted to areas not directly exposed to obstructive injury,” the team wrote.
A closer look found substantial accumulation of macrophages, immune cells involved in inflammation, in both cholestatic and non-cholestatic portions of untreated animals. Pioglitazone treatment prevented this macrophage buildup in the non-cholestatic liver region, but not the cholestatic portion. A similar pattern was found for genes involved in macrophage recruitment and inflammatory signaling.
Cholestatic regions also showed a persistent and pronounced ductular reaction, an abnormal increase in bile duct cells that can occur with liver injury, in both treated and untreated rats. Pioglitazone treatment prevented this response in the non-cholestatic region, as well as the accumulation of myofibroblasts, the cells that produce scar tissue.
Gene activity patterns improved with treatment
These beneficial effects were accompanied by reduced activity of pro-inflammatory and pro-fibrotic signaling pathways.
Finally, gene co-expression network analysis, which examines how genes are organized and interact with one another, showed that pioglitazone treatment resulted in a well-defined, coordinated pattern of gene activity in the non-cholestatic region of treated rats. This contrasted with the disorganized gene activity pattern seen in untreated animals.
In cholestatic regions of treated rats, the gene activity response to pioglitazone was limited, and the region remained largely unresponsive to treatment, “consistent with a stabilized fibro-inflammatory microenvironment,” the team wrote.
“This study demonstrates that [PPAR-gamma] agonism was associated with a region-dependent antifibrotic effect during segmental cholestasis,” the researchers concluded. “In contrast, fibrosis established within cholestatic lobes remains [resistant] to [PPAR-gamma] modulation.”
