Adipocyte Exosomes in the Pathogenesis of Non-Alcoholic Fatty Liver Disease
- Evan Nadler, MD
- Tatiana Iordanskaia, PhD
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) has been attributed to increased systemic inflammation and insulin resistance mediated by visceral adipose tissue. Exosomes are membrane-derived vesicles containing mRNA, miRNA, and proteins, which we postulated may be involve in obesity-related diseases. We hypothesized that adipocyte exosomes would integrate into HepG2 and hepatic stellate cell (HSC) lines and cause dysregulation of the TGF-ß pathway. Exosomes from obese and lean patients were isolated and fluorescently labeled, then applied to cultured hepatic cell lines. After incubation, culture slides were imaged to detect exosome uptake. In separate experiments, exosomes were applied to cultured cells and incubated 48-hours. Gene expression of TGF-ß pathway mediators was analyzed by PCR, and compared with cells which were not exposed to exosomes. Fluorescent-labeled exosomes integrated into both cell types and deposited in a peri-nuclear distribution. Exosome exposure caused increased TIMP-1 and Integrin αvβ -5 expression, and decreased MMP-7 and PAI-1 expression in to HepG2 cells, and increased expression of TIMP-1, TIMP-4, Smad-3, Integrins αvβ-5 and αvβ -8, and MMP-9 in HSCs. Exosomes from VAT integrate into liver cells and induce dysregulation of TGF-ß pathway members in vitro, and offers an intriguing possibility for the pathogenesis of NAFLD.