Serum amyloid A protein (SAA) is an apolipoprotein that can replace apolipoprotein A1 (apoA1) as the major apolipoprotein of HDL. Porcine hepatic SAA mRNA is increased by dietary docosahexaenoic acid (DHA) treatment. The purpose of this study was to investigate the role of SAA protein in regulating gene expression related to lipid metabolism in pigs. First, we demonstrated that the 100-micromol/L DHA treatment increased SAA and apoA1 mRNA expression in porcine hepatic cell cultures (P < 0.05). Secondly, we produced porcine SAA recombinant protein and found that the addition of SAA to porcine preadipocytes in culture stimulated interleukin-6 (IL-6) mRNA expression (P < 0.05), indicating a similar biological function of porcine SAA and human SAA. We also found PPARalpha and PPARgamma mRNA were decreased (40 and 60%, respectively) in differentiated adipocytes after treatment with 2 mumol/L SAA. SAA treatment also increased inflammatory cytokine gene expression (IL-6 and tumor necrosis factor alpha) and glycerol release (P < 0.05), indicating increased lipolysis. Because the expression of perilipin, a lipid droplet-protective protein, was reduced by the SAA treatment, we hypothesized that SAA increased lipolysis by decreasing the expression of perilipin, which would then allow an increase in hormone sensitive lipase activity. In conclusion, we demonstrated that the DHA-induced SAA gene expression decreased PPAR expression and consequently downregulated the expression of several genes involved in lipid metabolism. Accordingly, SAA may play a critical role in mediating the function of dietary DHA on lipid metabolism and could be a factor in regulating obesity.

Serum amyloid A (SAA) reduces fat deposition in adipocytes and hepatoma cells. Human SAA1 mRNA is increased by docosahexaenoic acid (DHA) treatment in human cells. These studies asked whether DHA decreases fat deposition through SAA1 and explored the mechanisms involved. We demonstrated that DHA increased human SAA1 and C/EBP␤ mRNA expression in human hepatoma cells, SK-HEP-1. Utilizing a promoter deletion assay, we found that a CCAAT/enhancer-binding protein ␤ (C/EBP␤)-binding site in the SAA1 promoter region between ؊242 and ؊102 bp was critical for DHA-mediated SAA1 expression. Mutation of the putative C/EBP␤-binding site suppressed the DHA-induced SAA1 promoter activity. The addition of the protein kinase A inhibitor H89 negated the DHA-induced increase in C/EBP␤ protein expression. The up-regulation of SAA1 mRNA and protein by DHA was also inhibited by H89. We also demonstrated that DHA increased protein kinase A (PKA) activities. These data suggest that C/EBP␤ is involved in the DHA-regulated increase in SAA1 expression via PKA-dependent mechanisms. Furthermore, the suppressive effect of DHA on triacylglycerol accumulation was abolished by H89 in SK-HEP-1 cells and adipocytes, indicating that DHA also reduces lipid accumulation via PKA. The observation of increased SAA1 expression coupled with reduced fat accumulation mediated by DHA via PKA suggests that SAA1 is involved in DHA-induced triacylglycerol breakdown. These findings provide new insights into the complicated regulatory network in DHA-mediated lipid metabolism and are useful in developing new approaches to reduce body fat deposition and fatty liver. Serum amyloid A (SAA)3 is a family of apolipoproteins mainly synthesized in mammalian liver. There are constitutive family members (SAA4) and acute-phase members (SAA1 and SAA2) that respond to tissue damage and inflammation. The acute-phase SAA is induced primarily by IL-1, tumor necrosis factor ␣, and IL-6 through the down-regulation of NF-B, CCAAT/enhancer-binding protein (C/EBP) family, and SAA activating factor (SAF) whose binding elements have been located and characterized in the acute-phase SAA promoter region (1). The SAA1 is considered to be a marker for obesity and cardiovascular disease because the expression of SAA1 is correlated well with the degree of obesity (2) and the risk of cardiovascular disease (3). However, the discoveries of the effect of SAA1 in lipid metabolism suggest that SAA1 is a mediator to reduce fat deposition. For example, several lipogenic enzymes, including acetyl-CoA carboxylase 1, lipoprotein lipase, and adipocyte fatty acid-binding protein, are reduced in adipocytes by SAA treatments (4). A glycerol-releasing effect of SAA can also be observed in porcine and human adipocytes (4, 5).The n-3 polyunsaturated fatty acids (PUFA) are beneficial in many chronic diseases, including obesity, coronary heart disease, and fatty livers. A high docosahexaenoic acid/eicosapentaenoic acid diet increases weight loss and decreases fat deposition in mice and humans (6, 7). The inta...

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