Treatment of cigarette smoke extract and condensate differentially potentiates palmitic acid-induced lipotoxicity and steatohepatitis in vitro.

Accumulative evidence showed that cigarette smoke (CS) detrimentally affects the pathogenesis of nonalcoholic steatohepatitis (NASH). The purpose of this study was to evaluate the effects of CS extract (CSE) or total particulate matter (TPM) on the in vitro steatohepatitis model using mouse primary hepatocytes treated with palmitic acid (PA) or PA plus LPS. Increased hepatocellular damage was observed in PA-treated hepatocytes with TPM or CSE treatment, but increased triglyceride level was only observed in PA plus LPS-treated hepatocytes with a high concentration of TPM. Also, expression levels of steatohepatitis-related genes such as TNF-α, NOS 2, and SREBP-1c were significantly increased after treatment of TPM. To further demonstrate the role of Kupffer cells (KCs) after CS extracts treatment, trans-well co-culture system of hepatocytes and KCs was utilized. The levels of inflammatory cytokines and the ratios of Bax/Bcl-2 (apoptosis-related genes) were markedly increased in co-cultured hepatocytes after TPM or CSE treatment. Interestingly, KCs activation was augmented in KCs upon treatment with CSE or TPM. Overall, our findings indicate that in vitro treatment with CSE or TPM differentially contributes to the severity of steatohepatitis by modulating steatohepatitis-related lipotoxicity and inflammation, which might be caused by KCs activation with subsequent induction of hepatocytes apoptosis.