The power of mass spectrometry to generate rapid, precise, and reproducible diagnostic information that complements genomic information and accelerates our understanding of the disease, is now ...becoming a reality.3,4 Mass spectrometry-based analysis can answer questions broadly falling into two categories. ...data will facilitate public health efforts for population screening, defining high-risk patients, tracking disease progression, and identifying sources of vulnerability that will permit treatment stratification and minimise or prevent future coronavirus pandemics. The COVID-19 MS Coalition is a collective mass spectrometry effort that will provide molecular level information on SARS-CoV-2 in the human host and reveal pathophysiological and structural information to treat and minimise COVID-19 infection.
Methylthioadenosine phosphorylase (MTAP), a key enzyme in the adenine and methionine salvage pathways, catalyzes the hydrolysis of methylthioadenosine (MTA), a compound suggested to affect pivotal ...cellular processes in part through the regulation of protein methylation. MTAP is expressed in a wide range of cell types and tissues, and its deletion is common to cancer cells and in liver injury. The aim of this study was to investigate the proteome and methyl proteome alterations triggered by MTAP deficiency in liver cells to define novel regulatory mechanisms that may explain the pathogenic processes of liver diseases. iTRAQ analysis resulted in the identification of 216 differential proteins (p < 0.05) that suggest deregulation of cellular pathways as those mediated by ERK or NFκB. R-methyl proteome analysis led to the identification of 74 differentially methylated proteins between SK-Hep1 and SK-Hep1+ cells, including 116 new methylation sites. Restoring normal MTA levels in SK-Hep1+ cells parallels the specific methylation of 56 proteins, including KRT8, TGF, and CTF8A, which provides a novel regulatory mechanism of their activity with potential implications in carcinogenesis. Inhibition of RNA-binding proteins methylation is especially relevant upon accumulation of MTA. As an example, methylation of quaking protein in Arg242 and Arg256 in SK-Hep1+ cells may play a pivotal role in the regulation of its activity as indicated by the up-regulation of its target protein p27kip1. The phenotype associated with a MTAP deficiency was further verified in the liver of MTAP± mice. Our data support that MTAP deficiency leads to MTA accumulation and deregulation of central cellular pathways, increasing proliferation and decreasing the susceptibility to chemotherapeutic drugs, which involves differential protein methylation. Data are available via ProteomeXchange with identifier PXD002957 (http://www.ebi.ac.uk/pride/archive/projects/PXD002957).
One-carbon metabolism (1CM) plays a central role in liver physiology, being the source of essential metabolites such as S-adenosylmethionine, the main alkylating agent in living cells, and ...glutathione, their most important nonenzymatic antioxidant defense. Impairment of 1CM in hepatocytes is a recognized factor associated to chronic liver disorders and hepatocellular carcinoma. With this in mind, we have proposed the concept of functional biomarker referring to a cellular pathway that can be systematically monitored as indicative of a particular physiological or pathological condition. Here we describe a targeted mass spectrometry (MRM) protocol to simultaneously quantify 13 1CM enzymes in liver tissue specimens.
Fibroblast growth factor 15/19 (FGF15/19), an enterokine that regulates synthesis of hepatic bile acids (BA), has been proposed to influence fat metabolism. Without FGF15/19, mouse liver regeneration ...after partial hepatectomy (PH) is severely impaired. We studied the role of FGF15/19 in response to a high fat diet (HFD) and its regulation by saturated fatty acids. We developed a fusion molecule encompassing FGF19 and apolipoprotein A-I, termed Fibapo, and evaluated its pharmacological properties in fatty liver regeneration.
mice were fed a HFD. Liver fat and the expression of fat metabolism and endoplasmic reticulum (ER) stress-related genes were measured. Influence of palmitic acid (PA) on
expression was determined in mice and in human liver cell lines. In vivo half-life and biological activity of Fibapo and FGF19 were compared. Hepatoprotective and proregenerative activities of Fibapo were evaluated in obese
mice undergoing PH.
Hepatosteatosis and ER stress were exacerbated in HFD-fed
mice. Hepatic expression of
was elevated in
mice, being reversed by FGF19 treatment. PA induced
expression in mouse ileum and human liver cells, and FGF19 protected from PA-mediated ER stress and cytotoxicity. Fibapo reduced liver BA and lipid accumulation, inhibited ER stress and showed enhanced half-life. Fibapo provided increased
mice survival and improved regeneration upon PH.
FGF15/19 is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator of
expression
Perioperative administration of Fibapo improves fatty liver regeneration.
The Human Proteome Project (HPP) annually reports on progress throughout the field in credibly identifying and characterizing the human protein parts list and making proteomics an integral part of ...multiomics studies in medicine and the life sciences. NeXtProt release 2018–01–17, the baseline for this sixth annual HPP special issue of the Journal of Proteome Research, contains 17 470 PE1 proteins, 89% of all neXtProt predicted PE1–4 proteins, up from 17 008 in release 2017–01–23 and 13 975 in release 2012–02–24. Conversely, the number of neXtProt PE2,3,4 missing proteins has been reduced from 2949 to 2579 to 2186 over the past two years. Of the PE1 proteins, 16 092 are based on mass spectrometry results, and 1378 on other kinds of protein studies, notably protein–protein interaction findings. PeptideAtlas has 15 798 canonical proteins, up 625 over the past year, including 269 from SUMOylation studies. The largest reason for missing proteins is low abundance. Meanwhile, the Human Protein Atlas has released its Cell Atlas, Pathology Atlas, and updated Tissue Atlas, and is applying recommendations from the International Working Group on Antibody Validation. Finally, there is progress using the quantitative multiplex organ-specific popular proteins targeted proteomics approach in various disease categories.
The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing ...accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP's tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.
According to the 2020 Metrics of the HUPO Human Proteome Project (HPP), expression has now been detected at the protein level for >90% of the 19 773 predicted proteins coded in the human genome. The ...HPP annually reports on progress made throughout the world toward credibly identifying and characterizing the complete human protein parts list and promoting proteomics as an integral part of multiomics studies in medicine and the life sciences. NeXtProt release 2020–01 classified 17 874 proteins as PE1, having strong protein-level evidence, up 180 from 17 694 one year earlier. These represent 90.4% of the 19 773 predicted coding genes (all PE1,2,3,4 proteins in neXtProt). Conversely, the number of neXtProt PE2,3,4 proteins, termed the “missing proteins” (MPs), was reduced by 230 from 2129 to 1899 since the neXtProt 2019–01 release. PeptideAtlas is the primary source of uniform reanalysis of raw mass spectrometry data for neXtProt, supplemented this year with extensive data from MassIVE. PeptideAtlas 2020–01 added 362 canonical proteins between 2019 and 2020 and MassIVE contributed 84 more, many of which converted PE1 entries based on non-MS evidence to the MS-based subgroup. The 19 Biology and Disease-driven B/D-HPP teams continue to pursue the identification of driver proteins that underlie disease states, the characterization of regulatory mechanisms controlling the functions of these proteins, their proteoforms, and their interactions, and the progression of transitions from correlation to coexpression to causal networks after system perturbations. And the Human Protein Atlas published Blood, Brain, and Metabolic Atlases.
Cholestasis is characterized by disrupted bile flow from the liver to the small intestine. Although etiologically different cholestasis displays similar symptoms, diverse factors can contribute to ...the progression of the disease and determine the appropriate therapeutic option. Therefore, stratifying cholestatic patients is essential for the development of tailor-made treatment strategies. Here, we have analyzed the liver proteome from cholestatic patients of different etiology. In total, 7161 proteins were identified and quantified, of which 263 were differentially expressed between control and cholestasis groups. These differential proteins point to deregulated cellular processes that explain part of the molecular framework of cholestasis progression. However, the clustering of different cholestasis types was limited. Therefore, a machine learning pipeline was designed to identify a panel of 20 differential proteins that segregate different cholestasis groups with high accuracy and sensitivity. In summary, proteomics combined with machine learning algorithms provides valuable insights into the molecular mechanisms of cholestasis progression and a panel of proteins to discriminate across different types of cholestasis. This strategy may prove useful in developing precision medicine approaches for patient care.
Fibroblast growth factor 15 (FGF15), FGF19 in humans, is a gut‐derived hormone and a key regulator of bile acids and carbohydrate metabolism. FGF15 also participates in liver regeneration after ...partial hepatectomy inducing hepatocellular proliferation. FGF19 is overexpressed in a significant proportion of human hepatocellular carcinomas (HCC), and activation of its receptor FGFR4 promotes HCC cell growth. Here we addressed for the first time the role of endogenous Fgf15 in hepatocarcinogenesis. Fgf15+/+ and Fgf15−/− mice were subjected to a clinically relevant model of liver inflammation and fibrosis‐associated carcinogenesis. Fgf15−/− mice showed less and smaller tumors, and histological neoplastic lesions were also smaller than in Fgf15+/+ animals. Importantly, ileal Fgf15 mRNA expression was enhanced in mice undergoing carcinogenesis, but at variance with human HCC it was not detected in liver or HCC tissues, while circulating FGF15 protein was clearly upregulated. Hepatocellular proliferation was also reduced in Fgf15−/− mice, which also expressed lower levels of the HCC marker alpha‐fetoprotein (AFP). Interestingly, lack of FGF15 resulted in attenuated fibrogenesis. However, in vitro experiments showed that liver fibrogenic stellate cells were not direct targets for FGF15/FGF19. Conversely we demonstrate that FGF15/FGF19 induces the expression of the pro‐fibrogenic and pro‐tumorigenic connective tissue growth factor (CTGF) in hepatocytes. These findings suggest the existence of an FGF15‐triggered CTGF‐mediated paracrine action on stellate cells, and an amplification mechanism for the hepatocarcinogenic effects of FGF15 via CTGF production. In summary, our observations indicate that ileal FGF15 may contribute to HCC development in a context of chronic liver injury and fibrosis.
What's new?
Fibroblast growth factor‐19 (FGF19), in rodents called FGF15, is a gut‐derived hormone recently implicated as a driver gene in liver carcinogenesis. Here, the authors show that Fgf15−/− mice develop less hepatocellular carcinoma and less liver fibrosis as compared to Fgf15+/+ littermates, underscoring the important role of the factor in liver damage and cancer development. Interestingly, Fgf15 expression is not detected in injured liver or carcinoma tissue, but is upregulated in the ileum and blood, pointing to a new gut‐liver axis involved in hepatocarcinogenesis.
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