Influence of Hepatocellular Senescence on Serum Amyloid A Expression and Response to Proinflammatory Cytokines under Steatotic Conditions.

Serum amyloid A (SAA) is an apolipoprotein produced mainly by the liver. SAA1 is upregulated during inflammation, whereas SAA4 is constitutively expressed and is generally considered to be unresponsive to proinflammatory cytokines. However, SAA4 has been identified as a gene whose expression increases in senescent hepatocytes. Cellular senescence has been implicated in the onset and progression of hepatic steatosis. This study aimed to clarify how cellular senescence influences SAA expression and cytokine responsiveness under steatotic conditions. An in vitro senescence-like model was established using HepG2 cells treated with doxorubicin. SAA4 transcript and secreted protein levels were upregulated in senescent cells, whereas SAA1 transcript levels remained very low. Senescent cells exhibited spontaneous lipid accumulation and an excessive response to oleic acid treatment. However, steatotic conditions did not alter the SAA4 transcript levels in either control or senescent cells. This result indicates that the upregulation of SAA4 persists independently of steatotic conditions. Proinflammatory cytokines robustly induced SAA1 expression and modestly increased SAA4 expression in control cells, amplifying these responses under lipid accumulation. Notably, senescence attenuated SAA induction in response to these cytokines, regardless of lipid accumulation. Although these findings were obtained in HepG2 cells, they provide a clue to understanding the regulation of SAA expression under non-basal conditions relevant to age-related liver diseases.