Enzymes of Fibrosis in Chronic Liver Disease

Abstract

Introduction: Liver fibrosis has been extensively studied at the cellular and molecular level, but very few data exist on the final enzymatic stages of collagen synthesis (prolyl hydroxylase, PH) and degradation (matrix metalloproteinases, MMPs), particularly in primary biliary cholangitis (PBC). Aim: We studied enzyme activities in liver tissue from patients with chronic liver diseases and compared them to normal livers. Patients: Eighteen patients with PBC of early and late stages (Ludwig’s classification) and seven on treatment with ursodeoxycholate (UDCA) were studied and compared to 34 patients with alcoholic liver disease (ALD), 25 patients with chronic viral liver disease and five normal biopsies. Sera were available from a total of 140 patients. Methods: The tritiated water released from the tritiated proline was measured in PH assessment. 14C intact and heat-denatured collagen substrates were used to measure collagenase and gelatinases, respectively. 3H Elastin was the substrate for elastase. In serum, ELISAs were used for MMP-1, TIMP-1, and TIMP-2 measurements while MMP-2 and MMP-9 were estimated by zymography. Results: PH was significantly increased in early and late PBC. Collagenase was reduced only in the late stages (p < 0.01), where the ratio PH/collagenase was increased. UDCA treatment restored values to almost normal. Gelatinases were reduced in late stages (p < 0.05). In contrast to PBC and ALD fibrosis, collagen synthesis is not increased in viral fibrosis. The balance shifted towards collagen deposition due to reduced degradation. Interestingly, gelatinolytic activity is not impaired in ALD. Elastase was similar to controls in all diseases studied. TIMP-1 was reduced in early PBC and viral and alcoholic hepatitis and cirrhosis (p < 0.001). Conclusions: (1) There is evidence that collagen synthesis increases in the early stages of PBC, but the collagenolytic mechanism may compensate for the increased synthesis. (2) In viral disease, fibrosis may be due to decreased degradation rather than increased synthesis. (3) The final biochemical stages of liver fibrosis may be quantitatively different according to underlying etiology.

Transcriptomic profiling identifies differentially expressed genes and related pathways associated with wound healing and cuproptosis-related genes in Ganxi goats

“…TIMP-1 is produced by macrophages and connective tissue cells, while TIMP-3 exists only in ECMs and can induce cell apoptosis ( 28 ). The imbalance of dynamic MMPs/TIMPs expression is associated with many diseases, such as liver fibrosis ( 29 ), wound healing disorders ( 30 ), and multiple cancers ( 31 ), which are often associated with cuproptosis ( 7 ). Wound excipients containing copper and zinc have been shown to promote fibroblast proliferation, increase collagen fibers, new arterial and venous capillaries, and enhance the wound healing process ( 32 ).…”

Extracellular matrix turnover: phytochemicals target and modulate the dual role of matrix metalloproteinases (MMPs) in liver fibrosis

“…The balance between the MMP/TIMP system largely governs the composition and remodeling of ECM. Under normal physiological conditions, various MMPs break down and reconstruct ECM with distinct substrate specificities (Geervliet & Bansal, 2020; Tsomidis et al, 2022). MMPs are produced as inactive zymogens and become active through intracellular, extracellular, or cell surface‐mediated proteolysis.…”

“…Several MMPs are pathologically involved in the dissolution and deposition of ECM in the early and late stages of liver fibrosis (Martinez‐Castillo et al, 2021). During physiological processes, the liver requires a balance in the expression of MMPs and tissue inhibitor of metalloproteinases (TIMP) to actively resolve fibrosis and maintain ECM homeostasis in response to reduced or increased ECM production and accumulation (Tsomidis et al, 2022). Various MMPs, such as MMP‐2, MMP‐3, MMP‐9, and MMP‐13, are matrix‐degrading enzymes transiently expressed by HSCs in the early stages of liver damage (Trojanek et al, 2020).…”

Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis?

“…Collagen is a major extracellular matrix in fibrotic tissues ( 3 ), and its synthesis increases in PBC. The metabolic regulation of collagen biosynthesis and degradation ( 4 ) may counteract with the increased synthesis in the early stages of PBC, but cannot compensate for the extensive collagen synthesis at the late stages of PBC, resulting in gradual development of liver cirrhosis ( 5 ). Therefore, the development of new therapies for PBC requires two distinct approaches.…”