Serum Amyloid A Induces Lipolysis by Downregulating Perilipin Through ERK1/2 and PKA Signaling Pathways

Abstract

Serum amyloid A (SAA) is not only an apolipoprotein, but also a member of the adipokine family with potential to enhance lipolysis. The purpose of this study was to explore how SAA facilitates lipolysis in porcine adipocytes. We found that SAA increased the phosphorylation of perilipin and hormone‐sensitive lipase (HSL) after 12‐h treatment and decreased perilipin expression after 24‐h treatment, and these effects were prevented by extracellular signal‐regulated kinase (ERK) or protein kinase A (PKA) inhibitors in primary adipocyte cell culture. SAA treatment decreased HSL and adipose triglyceride lipase (ATGL) expression. SAA treatment also activated ERK and PKA by increasing the phosphorylation of these kinases. Moreover, SAA significantly increased porcine adipocyte glycerol release and lipase activity, which was inhibited by either ERK (PD98059) or PKA (H89) inhibitors, suggesting that ERK and PKA were involved in mediating SAA enhanced lipolysis. SAA downregulated the expression of peroxisome proliferator‐activated receptor γ (PPARγ) mRNA, which was reversed by the ERK inhibitor. We performed a porcine perilipin promoter assay in differentiated 3T3–L1 adipocytes and found that SAA reduced the porcine perilipin promoter specifically through the function of its PPAR response element (PPRE), and this effect was reversed by the ERK inhibitor. These findings demonstrate that SAA‐induced lipolysis is a result of downregulation of perilipin and activation of HSL via ERK/PPARγ and PKA signaling pathways. The finding could lead to developing new strategies for reducing human obesity.

Apelin inhibits adipogenesis and lipolysis through distinct molecular pathways

“…Mutations in perilipin have been recently shown to increase lipolysis because of failing to sequester the interaction between ATGL and CGI-58 (Gandotra et al, 2011).It has been shown in perilipin null mice that basal lipolysis is elevated and the size of adipocytes is smaller (Martinez-Botas et al, 2000;Tansey et al, 2001). And a number of studies have demonstrated that increase (decrease) of perilipin via overexpression (gene knock-down) or hormonal/chemical stimulation (inhibition) results in reduced (increased) lipolysis and increased (reduced) lipid droplet size (Souza et al, 1998;Tansey et al, 2004;Sawada et al, 2010;Liu et al, 2011a).…”

LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity

“…However, the precise mechanisms that stimulate lipolysis in LS adipocytes remain to be established. Interestingly, one may hypothesize that the observed enhanced insulin-evoked MAPK activation in LS adipose tissue can sustain lipolysis, because MAPK can downregulate perilipin and activate HSL (35,36). Second, beyond an intrinsic effect on adipose tissue maintenance, reduced adiposity and DIO resistance of LS mice is also certainly due, at least in part, to their increased energy expenditure.…”

Effects of lipoic acid on lipolysis in 3T3-L1 adipocytes

“…Furthermore, a recent study reported that serum amyloid A stimulated lipolysis in parallel with a reduced HSL protein content. However, serum amyloid A caused a signifi cant increase of PKA-mediated HSL phosphorylation ( 44 ), suggesting opposite trends in HSL able to stimulate lipolysis, suggesting that the lipolytic actions are independent of the antioxidant capacities. Our data showed that despite the stimulatory effects of LA on lipolysis, HSL and ATGL gene expression and protein levels were inhibited after 24 h of LA treatment, together with a decrease in perilipin mRNA levels.…”