Cholesterol-induced leucine aminopeptidase 3 (LAP3) upregulation inhibits cell autophagy in pathogenesis of NAFLD

Abstract

Objectives: Leucine aminopeptidase 3 (LAP3), an M1 member of leucine aminopeptidase, was reported to be significantly upregulated in serum of nonalcoholic fatty liver disease (NAFLD) patients. However, the underlying mechanisms of LAP3 in NAFLD pathogenesis are still unknown. We aim to investigate the role of LAP3 in NAFLD pathogenesis and explore whether LAP3 has the potential to be a candidate biomarker in serum for NAFLD diagnosis. Methods: Liver tissues and serum from NASH rats, serum from patients with NAFLD were obtained to evaluate the LAP3 expression. Detection of GSSG/GSH, intracellular reactive oxygen species (ROS), and LC3 expression by elevation/ reduction of LAP3 expression to determine the role of LAP3 in NAFLD pathogenesis. Finally, the correlation analysis was conducted to evaluate the association between LAP3 expression and clinical indexes of NAFLD. Results: LAP3 expression was upregulated in hepatocytes and serum in E3 rats with NASH after 6-month HFD feeding. Cholesterol (CHO) dramatically upregulated LAP3 in LO2 cells, and then lead to negative regulation of autophagy. Moreover, LAP3 levels were also significantly increased in NAFLD patients compared to healthy controls. Correlation analysis revealed that serum LAP3 levels were positively correlated with TG, γ-glutamyltranspeptidase (GGT), and fasting blood glucose levels, while there was a negative correlation with HDL levels. Conclusions: The cholesterol-dependent upregulation of LAP3 in hepatocytes plays a critical role in the pathogenesis of NAFLD via inhibiting autophagy. Moreover, LAP3 could serve as a potential novel candidate biomarker for the diagnosis of NAFLD.

The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis

“…Overall, future studies are still needed to elucidate the global impacts of hyperglycemia on BeWo trophoblast inflammatory signaling pathways. Further, we observed an increased expression of LAP3 (involved in glutathione metabolism), a target that has previously found to be positively correlated with fasting blood glucose levels and has, by inhibiting autophagy, been implicated in the progression of Non-Alcoholic Fatty Liver Disease [90]. LAP3 has also been found to degrade glutathione (GSH), an important cellular antioxidant enzyme [91,92].…”

The link between theANPEPgene and type 2 diabetes mellitus may be mediated by the disruption of glutathione metabolism and redox homeostasis

“…No studies have investigated the levels of LAP3 in T2D. However, a recent study [114] showed that increased LAP3 in the rat liver and serum, as well as in humans, is associated with nonalcoholic fatty liver disease (NAFLD), a condition that regularly co-exists with type 2 diabetes [115]. Additionally, serum LAP3 levels were positively correlated with GGT and fasting blood glucose levels [114].…”

In Vitro Cytotoxic Effect of Aqueous Extracts from Leaves and Rhizomes of the Seagrass Posidonia oceanica (L.) Delile on HepG2 Liver Cancer Cells: Focus on Autophagy and Apoptosis

“…Among the signatures identified, some can be associated with autophagy down-regulation. In fact, hepatocytic autophagy is known to be suppressed by adenosine kinase-mediated AMP formation and leucyl aminopeptidase over-expression [ 77 , 78 ]; acyl-CoA binding (ACB) protein has also been described as a suppressor of autophagy in breast cancer cells via its binding ability to phosphatidylethanolamine of the phagophore membrane, resulting in the inhibition of LC3 lipidation [ 79 ]. Other protein signatures may be mainly associated with the onset of apoptosis, also linked to the impairment of mitochondrial function and modulation of the autophagic flux.…”