The multifaceted role of cathepsins in liver disease

Ruiz-Blazquez, Paloma; Pistorio, Valeria; Fernández-Fernández, María; Moles, Anna

doi:10.1016/j.jhep.2021.06.031

Cited by 27 publications

(28 citation statements)

References 80 publications

(47 reference statements)

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“…Among these enzymes, cathepsins are the most abundant proteases in vertebrates. They perform essential functions in all living organisms controlling homeostatic and pathological processes [48]. Interestingly, our results show that some cathepsins are upregulated in NPC hepatocytes (CTSD (fold change = 3.58), CTSB (fold change = 2.63), CTSH (fold change = 3.70), CTSZ (fold change = 3.91) and CTSS (fold change = 5.16)).…”

Section: Discussionmentioning

confidence: 69%

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Balboa

Marín

Oyarzún

et al. 2021

Cells

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Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

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Section: Discussionmentioning

confidence: 69%

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Balboa

Marín

Oyarzún

et al. 2021

Cells

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“…Neutrophil infiltration and degranulation are essential, well-known events during the inflammatory phase of the reperfusion injury. Several cathepsins, lysosomal proteases which primarily act as proteolytic enzymes involved in tissue remodeling [ 22 ], were among the proteins differing the most between groups. Besides neutrophil degranulation, cathepsins also regulate apoptosis, autophagy, and activation of hormones, with cathepsin C as an emblematic member of the cathepsin family.…”

Section: Discussionmentioning

confidence: 99%

Liver Graft Proteomics Reveals Potential Incipient Mechanisms behind Early Renal Dysfunction after Liver Transplantation

Norén

Oltean

Friman

et al. 2022

IJMS

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Acute kidney injury (AKI) is frequent after liver transplantation (LT) and correlates with later development of chronic kidney disease. Its etiology is multifactorial and combines pre-, intra-, and postoperative factors. Additionally, the liver graft itself seems an important element in the development of AKI, yet the detailed mechanisms remain unclear. We hypothesized that grafts of LT recipients developing significant early AKI may show distinct proteomic alterations, and we set out to identify proteome differences between LT recipients developing moderate or severe AKI (n = 7) and LT recipients without early renal injury (n = 7). Liver biopsies obtained one hour after reperfusion were assessed histologically and using quantitative proteomics. Several cytokines and serum amyloid A2 (SAA2) were analyzed in serum samples obtained preoperatively, 2–4 h, and 20–24 h after graft reperfusion, respectively. LT induced mild histological alterations without significant differences between groups but uniformly altered liver function tests peaking on postoperative day 1, with a trend towards more severe alterations in patients developing AKI. Global quantitative proteomic analysis revealed 136 proteins differing significantly in their expression levels (p < 0.05, FC 20%): 80 proteins had higher and 56 had lower levels in the AKI group. Most of these proteins were related to immune and inflammatory responses, host defense, and neutrophil degranulation. No differences between the studied pro- and anti-inflammatory cytokines or SAA2 between groups were found at any moment. Our results suggest that grafts of LT patients who develop early AKI reveal a distinct proteome dominated by an early yet prominent activation of the innate immunity. These findings support the hypothesis that AKI after LT may be favored by certain graft characteristics.

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“…CTSD has been found to be elevated in the plasma of patients with NASH compared to healthy individuals [ 14 ]. In addition, CTSB, CTSD, CTSL, and CTSS were found to be increased in HCC patients and associated with poor prognosis [ 11 , 42 , 43 ]. Ample studies have been performed regarding the role of cathepsins in several types of cancers.…”

Section: Nash-hcc Is a Global Health Problemmentioning

confidence: 99%

“…Lipids that accumulate in tissues other than adipose tissue enter the cells and build up in the lysosomes, which results in the release of cathepsins and other lysosomal enzymes. This process culminates in cell death, also known as lipotoxicity [ 42 ]. Therefore, cathepsins are thought to be involved in conditions where excess lipid accumulation plays a role.…”

Section: Mechanisms Of Cathepsins In Nafld/nashmentioning

confidence: 99%

All Roads Lead to Cathepsins: The Role of Cathepsins in Non-Alcoholic Steatohepatitis-Induced Hepatocellular Carcinoma

Mourik

Baumgartner

et al. 2022

Biomedicines

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Cathepsins are lysosomal proteases that are essential to maintain cellular physiological homeostasis and are involved in multiple processes, such as immune and energy regulation. Predominantly, cathepsins reside in the lysosomal compartment; however, they can also be secreted by cells and enter the extracellular space. Extracellular cathepsins have been linked to several pathologies, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). NASH is an increasingly important risk factor for the development of HCC, which is the third leading cause of cancer-related deaths and poses a great medical and economic burden. While information regarding the involvement of cathepsins in NASH-induced HCC (NASH-HCC) is limited, data to support the role of cathepsins in either NASH or HCC is accumulating. Since cathepsins play a role in both NASH and HCC, it is likely that the role of cathepsins is more significant in NASH-HCC compared to HCC derived from other etiologies. In the current review, we provide an overview on the available data regarding cathepsins in NASH and HCC, argue that cathepsins play a key role in the transition from NASH to HCC, and shed light on therapeutic options in this context.

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The multifaceted role of cathepsins in liver disease

Cited by 27 publications

References 80 publications

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Liver Graft Proteomics Reveals Potential Incipient Mechanisms behind Early Renal Dysfunction after Liver Transplantation

All Roads Lead to Cathepsins: The Role of Cathepsins in Non-Alcoholic Steatohepatitis-Induced Hepatocellular Carcinoma

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