Neutral ceramidase‐enriched exosomes prevent palmitic acid‐induced insulin resistance in H4IIEC3 hepatocytes

Abstract

Oversupply of free fatty acids such as palmitic acid (PA) from the portal vein may cause liver insulin resistance. Production of reactive oxygen species plays a pivotal role in PA‐induced insulin resistance in H4IIEC3 hepatocytes. Recently, we found that exosomes secreted from INS‐1 cells that were transfected with neutral ceramidase (NCDase) plasmids had raised NCDase activity; these NCDase‐enriched exosomes could inhibit PA‐induced INS‐1 cell apoptosis. Here, we showed that PA reduced insulin‐stimulated tyrosine phosphorylation of insulin receptor substrate 2 and decreased insulin‐stimulated uptake of the fluorescent glucose analog 2‐NBDG, confirming that insulin resistance occurred in PA‐treated H4IIEC3 cells. Moreover, NCDase‐enriched exosomes from INS‐1 cells rescued PA‐induced H4IIEC3 insulin resistance and blocked PA‐induced reactive oxygen species production in which ceramide was involved.

RETRACTED ARTICLE: Mesenchymal stem cell-derived exosomes exert ameliorative effects in type 2 diabetes by improving hepatic glucose and lipid metabolism via enhancing autophagy

“…Human embryo lung fibroblast (HELF) and human L-O2 cells were purchased from the China Cell Culture Center (Shanghai, China) and were maintained in Dulbecco's modified Eagle's medium (DMEM, Hyclone, UT, USA) with 10% FBS, within a 37°C incubator with 5% CO 2 . L-O2 cells were incubated with 0.25 mM of palmitic acid (PA, Sigma-Aldrich, USA) for 48 h to establish an insulin resistance cellular model [17]. L-O2 cells were pre-treated with HELF-derived exosomes (HDEs, 30 μg/ ml, normal control exosomes) or HucMDEs (30 μg/ml) prior to PA treatment.…”

Exosomal neutral sphingomyelinase 1 suppresses hepatocellular carcinoma via decreasing the ratio of sphingomyelin/ceramide

“…Published data show that exosomes play a role in immune escape, drug resistance, and tumor progression [33,34]. Moreover, our previous data show that exosomes act as carriers to transport enzymes to target cells or organs [35]. In this study, we found that NSMase1 expression and NSMase activity in exosomes isolated from HCC tissues and those isolated from HCC cell culture medium were significantly decreased.…”

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

“…The quantification of plasma ceramide as a biomarker could predict major adverse cardiac events [80][81][82][83]. Zhu and colleagues showed that ASAH2 treatment might overcome palmitic acid (PA)-induced insulin resistance and also block PA-induced oxidative stress where ceramide is involved (Table 3) [84,85]. Xie et al also demonstrated that ceramide depletion through the overexpression of acid ceramidase either in the liver or in adipose tissue ameliorates the ceramide-activated protein kinase C isoform PKCζ and therefore improves hepatic steatosis and insulin sensitivity [16].…”