5A]). Hepatic expression of SREBP-1c, ACC1, and FAS was higher in IL-6−/− mice but lower in IL-10−/− mice compared with those in
WT mice (Fig. 5A,B). Reduced expression of these genes in IL-10−/− mice was partially reversed in IL-10−/−IL-6−/− dKO mice (Fig. 5A,B). Activation of adenosine monophosphate-activated protein kinase (AMPK) plays a key role in controlling lipid metabolism by phosphorylating and subsequently inhibiting ACC and suppressing the expression of ACC and FAS through down-regulation of SREBP-1c.32 ACC is an important enzyme for fatty acid synthesis, which catalyzes the first step in de novo fatty acid biosynthesis by converting acetyl coenzyme A to malonyl coenzyme A. Malonyl coenzyme A acts as a potent inhibitor of fatty acid oxidation by inhibiting carnitine palmitoyltransferase 1 (CPT-1), BMN-673 which transports fatty acids into the mitochondria for oxidation.33, 34 As shown in Fig. 5, expression of activated (i.e., phosphorylated) AMPK (pAMPK) was significantly higher in IL-10−/− mice than that in WT mice in both the XL184 price STD and
HFD groups, whereas such up-regulation was diminished in IL-10−/−IL-6−/− mice. Expression of pAMPK was comparable between IL-6−/− mice and WT mice. Consistent with the elevated levels of pAMPK, IL-10−/− mice had higher levels of inhibited (i.e., phosphorylated) ACC1 (pACC1) compared with WT mice. Such elevated phosphorylated ACC1 was reduced in IL-10−/−IL-6−/− mice versus IL-10−/− mice. In addition, hepatic expression of CPT1 was higher in HFD-fed IL-10−/− mice compared with WT mice. An additional deletion of IL-6 reduced hepatic CPT1 expression in IL-10−/−IL-6−/− mice versus IL-10−/− mice. Expression of these lipid metabolism-associated genes were also examined in WT, IL-10−/−, and IL-10−/− STAT3Hep−/− mice (Fig. 6). Compared with WT mice, IL-10−/− mice had reduced expression of SREBP-1c, ACC1, and Exoribonuclease FAS but enhanced expression of pAMPK, pACC1, and CPT-1 in the liver. These
dysregulations were partially corrected in IL-10−/− STAT3Hep−/− mice. In this article, we have demonstrated that IL-10−/− mice have greater liver inflammatory response but less steatosis and liver injury compared with WT mice after feeding with an ETOH or HFD diet. Our data suggest that in our models, inflammatory response reduces rather than promotes steatosis through activation of hepatic IL-6/STAT3, which subsequently inhibits the expression of lipogenic genes (SREBP-1c, ACC1, and FAS). In concert, IL-6 up-regulates the expression of CPT-1 and activates AMPK, which in turn further attenuates the expression of SREBP-1c and its target genes and inhibits ACC1. We have integrated our findings in a model depicting the effects of inflammation on steatosis in IL-10−/− mice (Fig. 7).