Gut bacterial metabolites in hepatic lipotoxicity and non-alcoholic fatty liver disease

Our studies showed that TMA promotes lipogenic processes through upregulation of fmo genes expression (p<0.05). TMA treated hepatocytes had increased mRNA expression of cholesterol and triglycerides synthesis regulators: srebp2 and srebp1c (p<0.05) and their downstream target genes (p<0.05) comparing to untreated controls. This promoted elevated triglyceride and cholesterol contents in cell media and in the treated cells (p<0.05).

These changes were associated with the upregulation of miR-125a and miR-125b (p<0.05). miR-125 has been shown to target mRNA of an anti-inflammatory protein A20. A20 protein level was significantly decreased in the TMA treated AML12 compared to untreated ones. TMAO induces lipogenesis (p<0.05) and increase ER stress (p<0.05).

A. mucinphila (Akk) treatment of mice upregulated A20 protein level in liver while reduced level of miR-125b (p<0.05). This can be associated with AMUC_1100 membrane protein of Akk which showed to prevent TMA mediated reduction in A20 in vitro. <br> <br>Conclusion: TMA has a pro-lipogenic properties associated with FMOs activity which mediate miR-125a/b dependent A20 downregulation. On the other hand, TMAO has pro-lipogenic properties, while inducing ER stress.

TMA and TMAO effect on hepatocytes could be prevented by Akk treatment of mice or AMUC_1100 transfection of TMA treated AML12 cells.<br>