Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury

Abstract

ObjectiveLiver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression.Design and resultsPatients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl4-injected OpnHep transgenic yet it was less in wild type and almost absent in Opn−/− mice. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep) protected mice from CCl4-induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by Opn or Hmgb1 ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K–pAkt1/2/3 pathway to upregulate collagen-I.ConclusionsDuring liver fibrosis, the increase in OPN induces HMGB1, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.

Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis

“…Studies have shown that measuring OPN in the plasma of liver disease patients is an effective biomarker for assessing the severity of liver fibrosis [8–11]. Furthermore, it has been demonstrated that hepatocytes act as a major source of OPN, and act in a paracrine role in activating HSCs and increasing collagen-I production [12]. Multiples studies have found that neutralizing OPN abrogates the development of fibrosis [4, 5, 12–15].…”

“…Furthermore, it has been demonstrated that hepatocytes act as a major source of OPN, and act in a paracrine role in activating HSCs and increasing collagen-I production [12]. Multiples studies have found that neutralizing OPN abrogates the development of fibrosis [4, 5, 12–15]. In a murine model of thioacetamide (TAA)-induced hepatic fibrosis, OPN-knockout mice demonstrated less hepatic damage and a faster resolution of fibrosis [15].…”

Chronic hepatitis C virus infection and pathogenesis of hepatocellular carcinoma

“…The first involves the acetylation of HMGB1 by extracellular osteopontin (OPN), a stress sensor protein that is enhanced in liver disease and elevated in serum of patients who are at risk of HCC development [44]. Acetylated HMGB1 interacts with HDAC1/HDAC2 to promote collagen-I expression by HSCs and increase its histological deposition [45]. The second mechanism relies on the upregulation of the Gas6/Axl pathway in HSC leading to activation of these cells and liver fibrogenesis upon carbon tetrachloride-induced injury in mice [46].…”

“…The second mechanism relies on the upregulation of the Gas6/Axl pathway in HSC leading to activation of these cells and liver fibrogenesis upon carbon tetrachloride-induced injury in mice [46]. Importantly, the clinical relevance of both mechanisms was evidenced by the correlation between the severity of liver injury and increased expression of OPN/HMGB1 or Gas6/Axl, respectively, in HCV-infected patients [45,46]. However, additional clinical cohort studies may be required to corroborate the involvement of these processes in HCV pathogenesis.…”

Renal Denervation Attenuates Multi-Organ Fibrosis and Improves Vascular Remodeling in Rats with Transverse Aortic Constriction Induced Cardiomyopathy

“…Fibrosis in kidney results in chronic kidney disease [8]. Fibrosis in liver accounts for cirrhosis and hepatocellular carcinoma [9]. Simultaneously, vascular remodeling may lead to arteriosclerosis [10].…”