Elaidic acid induces hepatic lipid accumulation by inhibiting chaperone-mediated autophagy via the GAS5/miR-27b-3p/SNX10 axis.

Source: PubMed, NCBI / U.S. National Library of Medicine

The intake of industrial trans-fatty acids (iTFAs), particularly elaidic acid (EA), has been implicated in non-alcoholic fatty liver disease (NAFLD), yet the underlying mechanisms remain incompletely understood. Functional chaperone-mediated autophagy (CMA) is essential for maintaining cellular lipid homeostasis. We found that EA exposure reduced the protein level of the CMA rate-limiting component LAMP-2A and induced lipid accumulation in hepatocytes. Importantly, treatment with the CMA activator QX77 significantly alleviated EA-induced lipid accumulation, supporting a functional role for CMA in this process. Cathepsin A (CTSA) is a critical enzyme that promotes the degradation of the LAMP-2A protein. Our data showed that EA upregulated sorting nexin 10 (SNX10), which in turn facilitated CTSA maturation, leading to decreased LAMP-2A abundance. We further investigated the upstream regulatory mechanism of SNX10 from the perspective of competitive endogenous RNA (ceRNA). Bioinformatics analysis and dual-luciferase reporter assays confirmed the existence of the GAS5/miR-27b-3p/SNX10 axis. Long chain non-coding RNA (LncRNA) GAS5 upregulated SNX10 expression by competitively binding to miR-27b-3p. Together, these findings suggested CMA disruption as a possible contributor to EA-induced lipid accumulation and identified the GAS5/miR-27b-3p/SNX10 ceRNA network as a potential regulatory mechanism for CMA.