The roles and mechanisms of SASP in senescent hepatic stellate cells

It has recently become apparent that senescence-associated secretory phenotype (SASP) has crucial roles in promoting cancer development in various situations, including obesity-associated hepatocellular carcinoma (HCC)... [ view full abstract ]

It has recently become apparent that senescence-associated secretory phenotype (SASP) has crucial roles in promoting cancer development in various situations, including obesity-associated hepatocellular carcinoma (HCC) development in mice. We have previously reported that dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage.  The enterohepatic circulation of DCA provokes SASP in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumor-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen.  However, it remain unclear exactly how DCA provokes SASP in HSCs in obese mice.  Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a gram positive gut microbial component, collaborate with DCA to induce SASP in HSCs.  Interestingly, this was accompanied by aberrant activation of cytoplasmic DNA sensing pathway.  These results, together with the observation that inactivation of cytoplasmic DNA sensing machinery substantially reduces SASP and HCC development in obese mice, uncover an unexpected link between obesity-induced gut microbial metabolite and cytoplasmic DNA sensing machinery.  We believe that a better understanding of the molecular mechanisms involved will lead to new strategies for the prevention of obesity-associated HCC development.