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Virginia Pardo Marqués, Águeda González-Rodríguez, Ángela Martínez Valverde
exposed to the CM from macrophages or Kuppfer cells hepatocytes treated with CM-O, highlighting the absence
treated with oleate or palmitate, with a significant increase of oleate-mediated proinflammatory responses in the
or decrease, respectively, as compared to control macrophage-hepatocyte axis.
hepatocytes (treated with CM-B). This opposite response
was also evidenced in Akt phosphorylation (at both Ser In addition to inflammation, FFAs-induced lipotoxicity
473 and Thr 308), a critical node of insulin´s metabolic contributes to the pathogenesis of NAFLD, being saturated
actions in hepatic cells (41). Thus, these results suggested FFAs the more toxic lipid species (45-47). Although the
that oleate and palmitate induce different secretory evaluation of the apoptotic responses under inflammatory
responses in peripheral and liver resident macrophages and conditions was not the major goal of this study, we
this might differentially modulate insulin signaling in liver detected cleavage of caspase 3 in hepatocytes treated with
cells. In the light of these findings, the M1 polarization CM-P, suggesting that the signals derived from the
state induced by palmitate, reflected by elevated TNFa, macrophage M1 polarization are likely involved in
IL6, IL1ß and MCP1 in agreement to Samokhvalov et al. lipoapoptosis. This interesting issue deserves future
(26), was not observed in Kupffer cells loaded with oleate. research.
The absence of M1 polarization is critical to understand
the modulation of insulin signaling by oleate in Although PTP1B has been involved in obesity and
hepatocytes as will be discussed below. In fact, increased inflammation (48-50), this is the first study showing the
arginase 1, Mrc1, Mgl1 and IL10 levels reflects a M2 modulation of PTP1B protein levels by a macrophage-
profile of macrophages after oleate challenge in agreement derived lipid product from oleate since reduced levels of
with recent results reported by Camell et al. on the role of LTB4 in CM-O paralleled with decreased PTP1B and
dietary oleic acid in M2 macrophages polarization (42). enhancement of insulin-mediated IR tyrosine
phosphorylation in hepatocytes. These data might be of
The ER plays a central role in the determination of cell relevance since PTP1B has emerged as a therapeutic target
fate under conditions of stress. Increased ER stress has against obesity-mediated insulin resistance by its ability to
been shown to contribute to the development of NAFLD regulate peripheral (muscle and liver) insulin sensitivity
(17). In this regard, CM-P-treated hepatocytes rapidly (49, 51-56) as well as the central control of appetite and
activated the PERK branch of UPR by inducing PERK, energy expenditure (48, 57, 58). Based on that, our
eIF2a and JNK phosphorylation, resulting in increased ongoing research is focused on the modulation of PTP1B
CHOP expression. Under these experimental conditions, expression by bioactive lipid species (eicosanoids) in
STAT3 phosphorylation was also increased, this response hepatocytes.
is probably mediated by the proinflammatory cytokines
IL6 and IL1ß. Moreover, TNFa-mediating signaling might In summary, we have demonstrated a paracrine cross-
also boost JNK and p38 MAPK activation. The talk from macrophages/Kupffer cells to hepatocytes, which
convergence of all these proinflammatory signaling bears opposite differences depending on the polarization
cascades leads to a negative-cross talk with insulin state of the macrophages and the factors secreted by these
signaling resulting in the degradation of both IR and IRS1 immune cells as it has been manifested upon treatment
that agrees with results reported in hepatocytes treated with palmitate or oleate. To our knowledge and as
with palmitate (43, 44). Therefore, lower IR and IRS1 summarized in Figure 9, this is the first study providing
levels detected in hepatocytes stimulated with CM-P data of the beneficial effects of oleate in switching
evidence the contribution of the early activation of stress macrophages polarization to increase insulin sensitization
kinases in the reduced insulin-mediated Akt in hepatocytes through decreasing PTP1B. Therefore,
phosphorylation. Neither the early activation of stress targeting PTP1B is a therapeutic strategy to combat
kinases nor CHOP expression were detected in hepatic insulin resistance in obesity.
206 @Real Academia Nacional de Farmacia. Spain
