In both strains of mice, rapamycin inhibits HCC development and hepatic steatosis (14, 31) Our data demonstrate that starvation-induced LKB1 and AMPK phosphorylation requires TAK1 in hepatocytes, although the mechanism by which TAK1 controls LKB1 and AMPK activities remains elusive (10, 30)

In both strains of mice, rapamycin inhibits HCC development and hepatic steatosis (14, 31) Our data demonstrate that starvation-induced LKB1 and AMPK phosphorylation requires TAK1 in hepatocytes, although the mechanism by which TAK1 controls LKB1 and AMPK activities remains elusive (10, 30). TGF receptor signaling (5, 6) and are more dramatic than the phenotypes observed in mice with hepatocyte-specific deletion of IKK or IKK/NEMO (5, 7C9). TAK1 can also regulate AMPK activity through phosphorylation (10). Nutrient deprivation strongly activates AMPK, leading to the inhibition of mTOR complex 1 (mTORC1), a multifunctional protein kinase complex that regulates lipid biosynthesis, cellular proliferation, and autophagy (11, 12). AMPK can also stimulate autophagy through direct phosphorylation of ULK1 independently of mTORC1 (13). Under high nutrient conditions, when ATP levels are high, AMPK activity is inhibited, thereby activating mTORC1 and resulting in increased lipid synthesis in a SREBP-1cC and PPAR-dependent manner (12). Moreover, mTORC1 inhibits PPAR activity, which regulates mitochondrial functions and fatty acid -oxidation (FAO) (14). Hepatic FAO is impaired in mice with inactivated PPAR, SIRT1, or SIRT3 (15C17). These mice exhibit Rabbit Polyclonal to PDCD4 (phospho-Ser457) significant lipid deposition in the liver upon consuming a high-fat diet (HFD) or during fasting. AMPK activation and mTORC1 inhibition induce autophagy to remove and recycle cellular materials for biosynthesis or energy production when nutrients are limited. Autophagy promotes lipid degradation and prevents excessive lipid accumulation (18). It was suggested that TAK1 might contribute to the induction of autophagy through either the IKK complex or AMPK (10, 19). However, the physiological and pathophysiological significance of TAK1-dependent regulation of AMPK/mTORC1 signaling and autophagy and their involvement in lipid metabolism and HCC development in the liver remain elusive. In the present study, we determined that TAK1 in hepatocytes prevents excessive lipid accumulation through AMPK activation, mTORC1 inhibition, and autophagy. TAK1 also favors PPAR-mediated FAO through the inhibition of mTORC1. Upon HFD feeding, TAK1 activity prevents excessive hepatic lipid accumulation, injury, and inflammation. Correspondingly, restoration of autophagy with the mTORC1 inhibitor rapamycin suppresses hepatic steatosis, fibrosis, and HCC progression in (mice and their WT counterparts, but after 12 hours of U-101017 fasting, livers of mice became white. mice showed increased lipid accumulation in hepatocytes compared with that seen in their WT counterparts, particularly after fasting (Figure ?(Figure1,1, A and B). Hepatic triglycerides (TGs) in fasted mice were 3-fold higher than those in fasted WT mice, whereas plasma FFAs were similarly elevated in both fasted and WT mice (Figure ?(Figure1,1, C and D). These data indicate that although FFA release from adipose tissue is not affected by loss of hepatic TAK1 expression, the deposition of TGs in the liver is TAK1 dependent. In WT livers, nutrient deprivation strongly inhibited S6 phosphorylation, an established marker of mTORC1 activity (Figure ?(Figure1E).1E). In contrast, mice were fasted for 12 hours (= 5 U-101017 each). (A) Macroscopic appearance of livers of WT and mice before and after fasting. (B) Oil Red O staining of lipid droplets. Original magnification, 200. (C) Hepatic TG content and (D) serum levels of FFAs were measured. (E) Immunoblotting for total TAK1, p-S6, and total S6. Black bar, WT; gray bar, mice. Data are presented as the means SEM. * 0.05; ** 0.01. AMPK activation and autophagy are inhibited in Tak1C/C hepatocytes. Reduced p62/SQSTM1 expression, increased LC3B-II generation from LC3B-I, and formation of LC3B aggregates are markers of autophagy induction (21C23). We found that fasted U-101017 WT livers exhibited lower p62 manifestation and higher LC3B-II amounts and build up of LC3B dots than did fed WT livers (Number ?(Number2,2, A and B, and Supplemental Number 1, A and U-101017 B; supplemental material available on-line with this short article; doi:10.1172/JCI74068DS1). In contrast, livers exhibited much higher p62 manifestation and no LC3B-II manifestation or less LC3B aggregates than did WT livers (Number ?(Number2,2, A and.