Cathepsin L and B as Potential Markers for Liver Fibrosis: Insights From Patients and Experimental Models

Abstract

OBJECTIVES:Cathepsin L (CTSL) and B (CTSB) have a crucial role in extracellular matrix (ECM) degradation and tissue remodeling, which is a prominent feature of fibrogenesis. The aim of this study was to determine the role and clinical significance of these cathepsins in liver fibrosis.METHODS:Hepatic histological CTSL and CTSB expression were assessed in experimental models of liver fibrosis, patients with liver cirrhosis, chronic viral hepatitis, and controls by real-time PCR and immunohistochemistry. Plasma levels of CTSL and CTSB were analyzed in 51 liver cirrhosis patients (Child–Pugh stages A, B and C) and 15 controls.RESULTS:Significantly enhanced CTSL mRNA (P=0.02) and protein (P=0.01) levels were observed in the liver of carbon tetrachloride-treated mice compared with controls. Similarly, hepatic CTSL and CTSB mRNA levels (P=0.02) were markedly increased in Abcb4−/− (ATP-binding cassette transporter knockout) mice compared with wild-type littermates. Elevated levels of CTSL and CTSB were also found in the liver (P=0.001) and plasma (P<0.0001) of patients with hepatic cirrhosis compared with healthy controls. Furthermore, CTSL and CTSB levels correlated well with the hepatic collagen (r=0.5, P=0.007; r=0.64, P=0.0001). CTSL and CTSB levels increased with the Child–Pugh stage of liver cirrhosis and correlated with total bilirubin content (r=0.4/0.2; P≤0.05). CTSL, CTSB, and their combination had a high diagnostic accuracy (area under the curve: 0.91, 0.89 and 0.96, respectively) for distinguishing patients from controls.CONCLUSIONS:Our data demonstrate the overexpression of CTSL and CTSB in patients and experimental mouse models, suggesting their potential as diagnostic biomarkers for chronic liver diseases.

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

“…The expression of cathepsin L is highly dysregulated in several human diseases, including diabetes, AAI, abdominal aortic aneurysm, liver fibrosis, and cancers [13,[82][83][84][85]. Its involvement in numerous forms of highly invasive cancers is particularly noteworthy and is covered in great detail in recent reviews [25,26,[86][87][88].…”

“…The focus of this review is specifically on human cathepsin L, a ubiquitously expressed endopeptidase whose involvement in several human diseases has emerged in recent years. These include liver fibrosis, Type I and II diabetes, cardiac and bone, immune and kidney disorders [12][13][14][15][16][17][18][19][20][21][22][23][24] In addition, its role in a wide variety of highly invasive forms of cancer is The propeptides act as an important regulatory on/off switch as well as a folding catalyst in cathepsin activation. Not surprisingly, the nature of propeptides among cysteine cathepsins is highly divergent by both chain lengths and primary sequences.…”

“…Studies by Yasothornsrikul et al revealed that cathepsin L is the proteolytic processing enzyme that renders active metenkephalin from proenkephalin [81]. In another studies, the severity of symptoms due to antigen-induced arthritis (AAI) was significantly reduced in Ctsl−/− mice due to a weakened T helper cell population in thymus [82].Molecules 2020, 25, 698 5 of 41The expression of cathepsin L is highly dysregulated in several human diseases, including diabetes, AAI, abdominal aortic aneurysm, liver fibrosis, and cancers [13,[82][83][84][85]. Its involvement in numerous forms of highly invasive cancers is particularly noteworthy and is covered in great detail in recent reviews [25,26,[86][87][88].…”

Utilizing Experimental Mouse Model to Identify Effectors of Hepatocellular Carcinoma Induced by HBx Antigen

“…FSTL1 induces liver fibrosis through hepatic stellate cell activation; CTSB plays key roles in extracellular matrix (ECM) degradation and tissue remodeling, which drive hepatic stellate cell proliferation and promote fibrogenic potential [51]. Moreover, Manchanda and co-workers suggested the potential of using CTSB as a diagnostic biomarker for chronic liver diseases [52]. Indeed, these three proteins play important roles in liver fibrosis and our HBx mice did not develop liver tumors.…”

Synthesis and preliminary radiopharmacological characterisation of an 11C‐labelled azadipeptide nitrile as potential PET tracer for imaging of cysteine cathepsins

“…Cysteine cathepsins are important players in various human disease processes including diabetes, obesity, inflammatory, and autoimmune disorders, neurodegenerative, cardiovascular, and fibrotic diseases, and—most evidently—cancer . In the last two decades, these enzymes attracted a lot of interest as potential drug targets, and more recently, their imaging in the physiological context in vivo has come into focus …”