Abstract
Nonalcoholic steatohepatitis (NASH) is the critical stage of nonalcoholic fatty liver disease (NAFLD). The persistence of necroinflammatory lesions and fibrogenesis in NASH is the leading cause of liver cirrhosis and, ultimately, hepatocellular carcinoma. To date, the histological examination of liver biopsies, albeit invasive, remains the means to distinguish NASH from simple steatosis (NAFL). Therefore, a noninvasive diagnosis by serum biomarkers is eagerly needed. Here, by a proteomic approach, we analysed the soluble low-molecular-weight protein fragments flushed out from the liver tissue of NAFL and NASH patients. On the basis of the assumption that steatohepatitis leads to the remodelling of the liver extracellular matrix (ECM), NASH-specific fragments were in silico analysed for their involvement in the ECM molecular composition. The 10 kDa C-terminal fragment of the ECM protein vitronectin (VTN) was then selected as a promising circulating biomarker in discriminating NASH. The analysis of sera of patients provided these major findings: the circulating VTN fragment (i) is overexpressed in NASH patients and positively correlates with the NASH activity score (NAS); (ii) originates from the disulfide bond reduction between the V10 and the V65 subunits. In conclusion, V10 determination in the serum could represent a reliable tool for the noninvasive discrimination of NASH from simple steatosis.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the developed and developing countries with a global estimated median prevalence of 20% [1]
The fibrosis stage in Nonalcoholic steatohepatitis (NASH) patients was more advanced than in those affected by NASH from simple steatosis (NAFL)
Our analysis on sera of nonalcoholic fatty liver disease (NAFLD) patients showed that: (i) circulating V10 is overexpressed in NASH patients compared to NAFL patients and positively correlates with NASH activity score (NAS); (ii) circulating V75 is underexpressed in NASH patients compared to NAFL patients and negatively correlates with NAS and liver fibrosis; (iii) the V10/V75 ratio is a predictor of NAS score, independently from body mass index (BMI), ALT, and AST; (iv) circulating V10 originates from the disulfide bond reduction of the V75 clipped form
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the developed and developing countries with a global estimated median prevalence of 20% [1]. Most NAFLD patients have simple steatosis or nonalcoholic fatty liver (NAFL) with low inflammation, tissue damage, or liver fibrosis. 13% to 31% of the cases develop definite nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis and inflammation with ballooning, with or without fibrosis [2]. It is crucial to obtain a prompt diagnosis of NAFLD patients with NASH for an effective clinical management. The differentiation of NAFL from definite steatohepatitis and liver fibrosis in the whole spectrum of NAFLD is still based on the histological examination of liver biopsies to assign a grade and stage through scoring systems [4]. The histological evaluation of liver biopsies addresses the full spectrum of lesions of NAFLD, this procedure remains invasive and limited by sampling error, diagnostic accuracy, and hazard to the patients [7]
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