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Fibrocystic liver disease: novel concepts and translational perspectives.

ABSTRACT: Fibrocystic liver diseases (FLDs) comprise a heterogeneous group of rare diseases of the biliary tree, having in common an abnormal development of the embryonic ductal plate caused by genetically-determined dysfunctions of proteins expressed in the primary cilia of cholangiocytes (and therefore grouped among the "ciliopathies"). The ductal dysgenesis may affect the biliary system at multiple levels, from the small intrahepatic bile ducts [congenital hepatic fibrosis (CHF)], to the larger intrahepatic bile ducts [Caroli disease (CD), or Caroli syndrome (CS), when CD coexists with CHF], leading to biliary microhamartomas and segmental bile duct dilations. Biliary changes are accompanied by progressive deposition of abundant peribiliary fibrosis. Peribiliary fibrosis and biliary cysts are the fundamental lesions of FLDs and are responsible for the main clinical manifestations, such as portal hypertension, recurrent cholangitis, cholestasis, sepsis and eventually cholangiocarcinoma. Furthermore, FLDs often associate with a spectrum of disorders affecting primarily the kidney. Among them, the autosomal recessive polycystic kidney disease (ARPKD) is the most frequent, and the renal function impairment is central in disease progression. CHF, CD/CS, and ARPKD are caused by a number of mutations in polycystic kidney hepatic disease 1 (PKHD1), a gene that encodes for fibrocystin/polyductin, a protein of unclear function, but supposedly involved in planar cell polarity and other fundamental cell functions. Targeted medical therapy is not available yet and thus the current treatment aims at controlling the complications. Interventional radiology or surgical treatments, including liver transplantation, are used in selected cases.

SUBMITTER: Lasagni A

PROVIDER: S-EPMC7838530 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-? full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-? agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-?, and the number of Ki67- and TGF-?-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the treatment of fibrocystic liver disease in ARPKD patients.

Project description:Mitochondria are entrusted with the challenging task of providing energy through the generation of ATP, the universal cellular currency, thereby being highly flexible to different acute and chronic nutrient demands of the cell. The fact that mitochondrial diseases (genetic disorders caused by mutations in the nuclear or mitochondrial genome) manifest through a remarkable clinical variation of symptoms in affected individuals underlines the far-reaching implications of mitochondrial dysfunction. The study of mitochondrial function in genetic or non-genetic diseases therefore requires a multi-angled approach. Taking into account that the liver is among the organs richest in mitochondria, it stands to reason that in the process of unravelling the pathogenesis of liver-related diseases, researchers give special focus to characterizing mitochondrial function. However, mitochondrial dysfunction is not a uniformly defined term. It can refer to a decline in energy production, increase in reactive oxygen species and so forth. Therefore, any study on mitochondrial dysfunction first needs to define the dysfunction to be investigated. Here, we review the alterations of mitochondrial function in liver cirrhosis with emphasis on acutely decompensated liver cirrhosis and acute-on-chronic liver failure (ACLF), the latter being a form of acute decompensation characterized by a generalized state of systemic hyperinflammation/immunosuppression and high mortality rate. The studies that we discuss were either carried out in liver tissue itself of these patients, or in circulating leukocytes, whose mitochondrial alterations might reflect tissue and organ mitochondrial dysfunction. In addition, we present different methodological approaches that can be of utility to address the diverse aspects of hepatocyte and leukocyte mitochondrial function in liver disease. They include assays to measure metabolic fluxes using the comparatively novel Biolog's MitoPlates in a 96-well format as well as assessment of mitochondrial respiration by high-resolution respirometry using Oroboros' O2k-technology and Agilent Seahorse XF technology.

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Fibrocystic liver disease: novel concepts and translational perspectives.

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