Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a dominant cause of chronic liver disease, but the exact mechanism of progression from simple steatosis to nonalcoholic steatohepatitis (NASH) remains unknown. Here, we investigated the role of exosomes in NAFLD progression. Exosomes were isolated from a human hepatoma cell line treated with palmitic acid (PA) and their miRNA profiles examined by microarray. The human hepatic stellate cell (HSC) line (LX-2) was then treated with exosome isolated from hepatocytes. Compared with controls, PA-treated hepatocytes displayed significantly increased CD36 and exosome production. The microarray analysis showed there to be distinctive miRNA expression patterns between exosomes from vehicle- and PA-treated hepatocytes. When LX-2 cells were cultured with exosomes from PA-treated hepatocytes, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with exosomes from vehicle-treated hepatocytes. In conclusion, PA treatment enhanced the production of exosomes in these hepatocytes and changed their exosomal miRNA profile. Moreover, exosomes derived from PA-treated hepatocytes caused an increase in the expression levels of fibrotic genes in HSCs. Therefore, exosomes may have important roles in the crosstalk between hepatocytes and HSCs in the progression from simple steatosis to NASH.

Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China

“…Upregulation of CD36 expression increases fatty acid uptake resulting in excess lipid supply and subsequent lipid accumulation in lung and heart which can induce cardiac hypertrophy and contractile dysfunction. Studies have found that palmitic acid increases CD36 expression, and palmitoylation results in abnormal lipid accumulation in cells . Since we had a significant increase in circulating palmitate, the upregulation of CD36 may be a sequelae to the metabolite.…”

“…Studies have found that palmitic acid increases CD36 expression, and palmitoylation results in abnormal lipid accumulation in cells. 31 Since we had a significant increase in circulating palmitate, the upregulation of CD36 may be a sequelae to the metabolite. In addition, we have found that the levels of 2-Octenoylcarnitine and 9-decenoylcarnitine were decreased in the CHD-PAH patients.…”

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

“…Saturation of hepatocytes with lipids in NASH contributes to the production of lipotoxic compounds and cell death due to mitochondrial dysfunction and ROS production [88]. Finally, the treatment of hepatocytes with palmitic acid does not only induce apoptosis but also enhances the ability of hepatocyte-derived exosomes to activate HSCs [89].…”

Exosomes and diabetes

“…Interestingly, exosomes isolated from adipose explants obtained from obese patients can enter primary hepatocytes in vitro and induce deregulation of the transforming growth factor β (TGFβ) pathway . On the other hand, EVs released by primary murine hepatocytes or HepG2 cells during a lipotoxic challenge with palmitic acid are internalized by hepatic stellate cells in vitro, resulting in efficiently transferred miRNAs, including miR‐128‐3p , miR‐122 and miR‐192 , and suppression of PPARγ, and activation of the expression of fibrotic genes . Moreover, repeated injection of exosome‐like particles released by hepatic immature myeloid cells from obese mice causes an accumulation of CD11b cells in the liver of the receptor mice, and these cells release pro‐inflammatory cytokines and induce natural killer T cell apoptosis .…”