Molecular Mechanisms of Isolated Polycystic Liver Diseases.
Ontology highlight
ABSTRACT:
SUBMITTER: Yu Z
PROVIDER: S-EPMC9104337 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Molecular Mechanisms of Isolated Polycystic Liver Diseases.
Yu Ziqi Z Shen Xiang X Hu Chong C Zeng Jun J Wang Aiyao A Chen Jianyong J
Frontiers in genetics 20220426
Polycystic liver disease (PLD) is a rare autosomal dominant disorder including two genetically and clinically distinct forms: autosomal dominant polycystic kidney disease (ADPKD) and isolated polycystic liver disease (PCLD). The main manifestation of ADPKD is kidney cysts, while PCLD has predominantly liver presentations with mild or absent kidney cysts. Over the past decade, <i>PRKCSH</i>, <i>SEC63</i>, <i>ALG8</i>, and <i>LRP5</i> have been candidate genes of PCLD. Recently, more candidate gen ...[more]
Similar Datasets
Project description:Polycystic liver diseases are genetic disorders characterized by progressive bile duct dilatation and/or cyst development. The large volume of hepatic cysts causes different symptoms and complications such as abdominal distension, local pressure with back pain, hypertension, gastro-oesophageal reflux and dyspnea as well as bleeding, infection and rupture of the cysts. Current therapeutic strategies are based on surgical procedures and pharmacological management, which partially prevent or ameliorate the disease. However, as these treatments only show short-term and/or modest beneficial effects, liver transplantation is the only definitive therapy. Therefore, interest in understanding the molecular mechanisms involved in disease pathogenesis is increasing so that new targets for therapy can be identified. In this Review, the genetic mechanisms underlying polycystic liver diseases and the most relevant molecular pathways of hepatic cystogenesis are discussed. Moreover, the main clinical and preclinical studies are highlighted and future directions in basic as well as clinical research are indicated.
| S-EPMC4526263 | biostudies-literature
Project description:Autosomal dominant (AD) and autosomal recessive (AR) polycystic kidney diseases (PKD) are severe multisystem genetic disorders characterized with formation and uncontrolled growth of fluid-filled cysts in the kidney, the spread of which eventually leads to the loss of renal function. Currently, there are no treatments for ARPKD, and tolvaptan is the only FDA-approved drug that alleviates the symptoms of ADPKD. However, tolvaptan has only a modest effect on disease progression, and its long-term use is associated with many side effects. Therefore, there is still a pressing need to better understand the fundamental mechanisms behind PKD development. This review highlights current knowledge about the fundamental aspects of PKD development (with a focus on ADPKD) including the PC1/PC2 pathways and cilia-associated mechanisms, major molecular cascades related to metabolism, mitochondrial bioenergetics, and systemic responses (hormonal status, levels of growth factors, immune system, and microbiome) that affect its progression. In addition, we discuss new information regarding non-pharmacological therapies, such as dietary restrictions, which can potentially alleviate PKD.
| S-EPMC8456103 | biostudies-literature
Project description:Liver diseases are caused by different etiological agents, mainly alcohol consumption, viruses, drug intoxication or malnutrition. Frequently, liver diseases are initiated by oxidative stress and inflammation that lead to the excessive production of extracellular matrix (ECM), followed by a progression to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). It has been reported that some natural products display hepatoprotective properties. Naringenin is a flavonoid with antioxidant, antifibrogenic, anti-inflammatory and anticancer properties that is capable of preventing liver damage caused by different agents. The main protective effects of naringenin in liver diseases are the inhibition of oxidative stress, transforming growth factor (TGF-β) pathway and the prevention of the transdifferentiation of hepatic stellate cells (HSC), leading to decreased collagen synthesis. Other effects include the inhibition of the mitogen activated protein kinase (MAPK), toll-like receptor (TLR) and TGF-β non-canonical pathways, the inhibition of which further results in a strong reduction in ECM synthesis and deposition. In addition, naringenin has shown beneficial effects on nonalcoholic fatty liver disease (NAFLD) through the regulation of lipid metabolism, modulating the synthesis and oxidation of lipids and cholesterol. Moreover, naringenin protects from HCC, since it inhibits growth factors such as TGF-β and vascular endothelial growth factor (VEGF), inducing apoptosis and regulating MAPK pathways. Naringenin is safe and acts by targeting multiple proteins. However, it possesses low bioavailability and high intestinal metabolism. In this regard, formulations, such as nanoparticles or liposomes, have been developed to improve naringenin bioavailability. We conclude that naringenin should be considered in the future as an important candidate in the treatment of different liver diseases.
| S-EPMC5922990 | biostudies-literature
Project description:Background: Polycystic liver diseases (PLD) are genetic disorders characterized by progressive growth of numerous liver cysts, causing significant morbidity. Previous studies revealed genes affecting protein biogenesis and more recently, protein SUMOylation, a posttranslational modification (PTM), has been implicated in PLD pathobiology. On the other hand, protein NEDDylation is a newly-characterized PTM, modulating a plethora of biological processes and its dysregulation is associated with development and progression of several human diseases. In this regard, the role of NEDDylation in PLD remains elusive and unraveling its role in the pathogenesis of these genetic disorders could open new avenues for the development of novel treatments in the future. Objective: To explore the role of protein NEDDylation in PLD and its potential therapeutic regulatory value. Methods: Expression and function of NEDDylation, including response to Pevonedistat (first-in-class selective inhibitor of the NEDDylation E1 enzyme NAE1), were assessed in vitro. Proteomic analyses of immunoprecipitated NEDDylated proteins were performed by mass spectrometry.
2022-02-16 | PXD022571 | Pride
Project description:Chronic liver disease (CLD) is a continuous process that causes a reduction of liver function lasting more than six months. CLD includes alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), chronic viral infection, and autoimmune hepatitis, which can lead to liver fibrosis, cirrhosis, and cancer. Liver inflammation and oxidative stress are commonly associated with the development and progression of CLD. Molecular signaling pathways such as AMP-activated protein kinase (AMPK), C-Jun N-terminal kinase, and peroxisome proliferator-activated receptors (PPARs) are implicated in the pathogenesis of CLD. Therefore, antioxidant and anti-inflammatory agents from natural products are new potent therapies for ALD, NAFLD, and hepatocellular carcinoma (HCC). In this review, we summarize some powerful products that can be potential applied in all the stages of CLD, from ALD/NAFLD to HCC. The selected agents such as β-sitosterol, curcumin, genistein, and silymarin can regulate the activation of several important molecules, including AMPK, Farnesoid X receptor, nuclear factor erythroid 2-related factor-2, PPARs, phosphatidylinositol-3-kinase, and lysyl oxidase-like proteins. In addition, clinical trials are undergoing to evaluate their efficacy and safety.
| S-EPMC10011909 | biostudies-literature
Project description:Autosomal dominant polycystic liver disease (ADPLD) is a distinct clinical and genetic entity that can occur independently from autosomal dominant polycystic kidney disease (ADPKD). We previously studied two large kindreds and reported localization of a gene for ADPLD to an approximately 8-Mb region, flanked by markers D19S586/D19S583 and D19S593/D19S579, on chromosome 19p13.2-13.1. Expansion of these kindreds and identification of an additional family allowed us to define flanking markers CA267 and CA048 in an approximately 3-Mb region containing >70 candidate genes. We used a combination of denaturing high-performance liquid chromatography (DHPLC) heteroduplex analysis and direct sequencing to screen a panel of 15 unrelated affected individuals for mutations in genes from this interval. We found sequence variations in a known gene, PRKCSH, that were not observed in control individuals, that segregated with the disease haplotype, and that were predicted to be chain-terminating mutations. In contrast to PKD1, PKD2, and PKHD1, PRKCSH encodes a previously described human protein termed "protein kinase C substrate 80K-H" or "noncatalytic beta-subunit of glucosidase II." This protein is highly conserved, is expressed in all tissues tested, and contains a leader sequence, an LDLa domain, two EF-hand domains, and a conserved C-terminal HDEL sequence. Its function may be dependent on calcium binding, and its putative actions include the regulation of N-glycosylation of proteins and signal transduction via fibroblast growth-factor receptor. In light of the focal nature of liver cysts in ADPLD, the apparent loss-of-function mutations in PRKCSH, and the two-hit mechanism operational in dominant polycystic kidney disease, ADPLD may also occur by a two-hit mechanism.
| S-EPMC1180260 | biostudies-literature
Project description:Biliary cysts in adult patients affected by polycystic liver disease are lined by cholangiocytes that proliferate, suggesting that initiation of cyst formation depends on proliferation. Here, we challenge this view by analyzing cyst-lining cell proliferation and differentiation in Cpk mouse embryos and in livers from human fetuses affected by Autosomal Recessive Polycystic Kidney Disease (ARPKD), at early stages of cyst formation. Proliferation of fetal cholangiocyte precursors, measured by immunostaining in human and mouse livers, was low and did not differ between normal and ARPKD or Cpk livers, excluding excessive proliferation as an initiating cause of liver cysts. Instead, our analyses provide evidence that the polycystic livers exhibit increased and accelerated differentiation of hepatoblasts into cholangiocyte precursors, eventually coalescing into large biliary cysts. Lineage tracing experiments, performed in mouse embryos, indicated that the cholangiocyte precursors in Cpk mice generate cholangiocytes and periportal hepatocytes, like in wild-type animals. Therefore, contrary to current belief, cyst formation in polycystic liver disease does not necessarily depend on overproliferation. Combining our prenatal data with available data from adult livers, we propose that polycystic liver can be initiated by proliferation-independent mechanisms at a fetal stage, followed by postnatal proliferation-dependent cyst expansion.
| S-EPMC4488361 | biostudies-literature
Project description:Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs and the development of new therapies. Studies of autosomal dominant and recessive polycystic kidney diseases converge on molecular mechanisms of cystogenesis, including ciliary abnormalities and intracellular calcium dysregulation, ultimately leading to increased proliferation, apoptosis and dedifferentiation. Here we review the pathobiology of PKD, highlighting recent progress in elucidating common molecular pathways of cystogenesis. We discuss available models and challenges for therapeutic discovery as well as summarize the results from preclinical experimental treatments targeting key disease-specific pathways.
| S-EPMC2775119 | biostudies-other
Project description:Infection susceptibility, poor vaccination efficacy, age-related disease onset, and neoplasms are linked to innate and adaptive immune dysfunction that accompanies aging (known as immunosenescence). During aging, organisms tend to develop a characteristic inflammatory state that expresses high levels of pro-inflammatory markers, termed inflammaging. This chronic inflammation is a typical phenomenon linked to immunosenescence and it is considered the major risk factor for age-related diseases. Thymic involution, naïve/memory cell ratio imbalance, dysregulated metabolism, and epigenetic alterations are striking features of immunosenescence. Disturbed T-cell pools and chronic antigen stimulation mediate premature senescence of immune cells, and senescent immune cells develop a proinflammatory senescence-associated secretory phenotype that exacerbates inflammaging. Although the underlying molecular mechanisms remain to be addressed, it is well documented that senescent T cells and inflammaging might be major driving forces in immunosenescence. Potential counteractive measures will be discussed, including intervention of cellular senescence and metabolic-epigenetic axes to mitigate immunosenescence. In recent years, immunosenescence has attracted increasing attention for its role in tumor development. As a result of the limited participation of elderly patients, the impact of immunosenescence on cancer immunotherapy is unclear. Despite some surprising results from clinical trials and drugs, it is necessary to investigate the role of immunosenescence in cancer and other age-related diseases.
| S-EPMC10182360 | biostudies-literature
Project description:Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases.
| S-EPMC5409105 | biostudies-literature