This antisteatotic effect was probably the result of a combination of effects on key mechanisms driving the progression to hepatic steatosis,

especially those related to insulin resistance. In this regard, Alox15 deletion in ApoE−/− mice resulted in significant improvements in glucose and insulin tolerance tests in parallel with reduced JNK phosphorylation, an established marker of insulin resistance. Moreover, Alox15 disruption augmented phosphorylation of AMPK, a master regulator of glucose and lipid homeostasis, normalized the hepatic glycogen content, and up-regulated the expression of IRS-2. Given that we did not detect changes in fasting glucose, these findings are consistent with the notion that the effects on fasting glucose in ApoE−/− Alisertib order mice are modest, whereas effects on glucose tolerance and insulin tolerance are more pronounced.36 Additionally, the antisteatotic effect associated with Alox15 disruption in ApoE−/− Ivacaftor datasheet mice was related to insulin-sensitizing effects in adipose tissue. Indeed, the insulin-resistant adipokines MCP-1, TNFα, IL-6, and resistin

were significantly repressed, whereas the expression of GLUT-4 was induced in ApoE−/−/12/15-LO−/− mice. Overall, the genetic disruption of Alox15 rendered similar effects on hepatic insulin signaling to those reported in previous studies in muscle and adipose tissues and are consistent with the role of 12/15-LO as a positive modulator of the onset of insulin resistance.9, 10, 13-16 It is important to note that the antisteatotic effects accompanying Alox15 disruption in ApoE−/− mice occurred in the absence of changes in liver weight, a phenomenon that has been documented.27, 37 The mechanisms by which hepatic steatosis does not translate into increased liver weight in ApoE−/− mice are presently unknown, but it can be speculated that the ApoE protein, in addition to its role

in lipoprotein clearance and very low-density lipoprotein assembly–secretion, also modulates the chemical composition of the hepatic tissue. Moreover, disruption of Alox15 in ApoE−/− mice did not affect serum cholesterol elevations, over suggesting that amelioration of liver injury in this model is independent of serum cholesterol levels. Although this is an intriguing observation, it is in line with previous publications in which deletion of Alox15 in ApoE−/− mice did not induce changes in serum cholesterol levels.11, 12, 38 Finally, it is also important to recognize that the antisteatotic effects accompanying the disruption of Alox15 in ApoE−/− mice differ slightly from those observed after disruption of Alox5 in these mice.7 In particular, disruption of the Alox5 gene significantly reduced hepatic inflammation without modifying the degree of hepatic steatosis,7 whereas the current study demonstrates that disruption of the Alox15 gene markedly reduces both parameters of liver injury. These results suggest that in terms of NAFLD, 12/15-LO appears to be the most relevant LO pathway.