In addition to regulating the activation of nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK), TGF-β activated kinase 1 (TAK1) also upregulates the activation of AMP-activated protein kinase (AMPK) and autophagy. In the liver, TAK1-mediated autophagy plays a role in preventing excessive lipid accumulation induced by starvation and fat overload. TAK1-mediated autophagy and inhibition of mechanistic target of rapamycin complex 1 (mTORC1) prevent liver fibrosis and tumor development

Seki, Ekihiro

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UCLAUCLA Previously Published WorksTitleTAK1-dependent autophagy: A suppressor of fatty liver disease and hepatic oncogenesisPermalinkhttps://escholarship.org/uc/item/8rv913x1JournalMolecular & Cellular Oncology, 1(4)ISSN2372-3548AuthorSeki, EkihiroPublication Date2014-12-08DOI10.4161/23723548.2014.968507 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaTAK1-dependent autophagy: A suppressor offatty liver disease and hepatic oncogenesisEkihiro Seki*Division of Gastroenterology; Department of Medicine and Surgery; University of California, San Diego; La Jolla, CA USAKeywords: AMPK, HCC, mTORC1, NASH, PPARaAbbreviations: AMPK, AMP-activated protein kinase; FAO, fatty acid oxidation; IKK, IkB kinase; JNK, c-Jun N-terminal kinase(JNK); LC3B, microtubule-associated protein 1 light chain 3 b; LKB1, liver kinase B1; NF-kB, nuclear factor kB; mTORC1,mechanistic target of rapamycin complex 1; HFD, high-fat diet; PPAR, peroxisome proliferator-activated receptor; TAK1, TGF-bactivated kinase 1; Tak1DHEP mice, hepatocyte-specific Tak1-deficient mice; TLR, Toll-like receptor; ULK1, unc-51 like autophagyactivating kinase; WT, wild-typeIn addition to regulating the activation of nuclear factor (NF)-kB and c-Jun N-terminal kinase (JNK), TGF-b activatedkinase 1 (TAK1) also upregulates the activation of AMP-activated protein kinase (AMPK) and autophagy. In the liver,TAK1-mediated autophagy plays a role in preventing excessive lipid accumulation induced by starvation and fatoverload. TAK1-mediated autophagy and inhibition of mechanistic target of rapamycin complex 1 (mTORC1) preventliver fibrosis and tumor development.Main TextTGF-b activated kinase 1 (TAK1), alsoknown as MAP3K7, is a serine/threoninekinase that belongs to the MAP3K family.In the signaling pathways of IL-1b, toll-like receptors (TLRs), TNFa, and TGF-b, TAK1 regulates the activation ofnuclear factor (NF)-kB and c-Jun N-ter-minal kinase (JNK).1 To examine thephysiological role of TAK1 in the liver,we generated hepatocyte-specific Tak1-deficient (Tak1DHEP) mice. Surprisingly,these mice develop spontaneous liver dam-age that leads to chronic liver inflamma-tion, fibrosis, and carcinogenesis.2 Theablation of Tak1 in hepatocytes promoteshepatocyte apoptosis and compensatoryhepatocyte proliferation due to failure toactivate the survival function of NF-kB.This aberrant hepatocyte regeneration, incombination with chronic liver inflamma-tion, ultimately results in the developmentof hepatocellular carcinoma in TAK1DHEPmice. However, another group reportedthat additional deletion of Ikbkg (alsoknown as Nemo), an essential modulatorof IkB kinase (IKK) and NF-kB activa-tion, reduces the spontaneous liver dam-age, inflammation, fibrosis, and cancer inTak1DHEP mice.3 This suggests that mech-anisms regulated by TAK1 other than theNF-kB pathway are responsible for theregulation of the liver pathology thatdevelops in Tak1DHEP mice.Several studies have reported that TAK1also activates AMP-activated protein kinase(AMPK) and autophagy.4 Our recent workdemonstrates the pathophysiological role ofTAK1-mediated autophagy in the liver.Fasting is a physiological inducer of autoph-agy in the liver. Fasted wild-type (WT) miceshow induction of hepatic autophagyaccompanied by decreased expression ofp62 (also known as sequestosome orSQSTM11) and activity of mechanistic tar-get of rapamycin complex 1 (mTORC1).To our surprise, hepatic Tak1 deficiencysuppressed autophagy induction and res-cued the decrease in p62 expression andmTORC1 activity upon fasting.5 Nutrientdeprivation or sensing an increased AMP/ATP ratio activates AMPK through liverkinase B 1 (LKB1), which directly and indi-rectly phosphorylates unc-51 like autophagyactivating kinase (ULK1) and subsequentlyinduces autophagy. We found that starva-tion-induced phosphorylation of LKB1,AMPK, and ULK1 and autophagy areTAK1-dependent in hepatocytes. Usingmicrotubule-associated protein 1 light chain3b (LC3B)-GFP transgenic mice, we foundthat basal levels of conversion of LC3BI toLC3BII protein, free GFP generation fromthe LC3B-GFP fusion protein, and mRNAlevels of autophagy-related genes (e.g., Atg3,Atg5, and Ulk1) are downregulated inTak1-deficient livers.5 This indicates thatTAK1 regulates not only autophagy inducedthrough AMPK activation, but also basalautophagy through transcriptional controlof the expression of autophagy-related genes.A recent report demonstrated that TAK1also mediates autophagy through S6K1independently of AMPK, which may beanother mechanism for the regulation ofbasal autophagy through TAK1.6© Ekihiro Seki*Correspondence to: Ekihiro Seki; Email: ekseki@ucsd.eduSubmitted: 08/19/2014; Revised: 08/20/2014; Accepted: 08/20/2014http://dx.doi.org/10.4161/23723548.2014.968507This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Themoral rights of the named author(s) have been asserted.www.landesbioscience.com e968507-1Molecular & Cellular OncologyMolecular & Cellular Oncology 1:4, e968507; October/November/December 2014; Published with license by Taylor & Francis Group, LLCAUTHOR'S VIEWAMPK and mTORC1 are suggested tobe downstream of TAK1. Indeed, overex-pression of a constitutively active form ofAMPK and treatment with rapamycin, anmTORC1 inhibitor, induces autophagyin Tak1-deficient hepatocytes.5 Rapamy-cin treatment of TAK1-deficient hepato-cytes significantly induces autophagy, butto a lower level than that in WT cells.This suggests that the regulation ofautophagy by TAK1 is modulated notonly by AMPK and mTORC1, but alsoby other pathways such as IKK signaling,as reported previously.7 A physiologicalfunction of TAK1-mediated autophagy isto prevent excessive lipid accumulationthrough lipophagy, a type of autophagythat degrades intracellular lipid droplets.Fasting increases hepatic uptake of circu-lating fat released from peripheral fat tis-sues, but hepatic fat accumulation istightly regulated by lipophagy to preventexcessive fat accumulation. In contrast,upon fasting the livers of Tak1DHEP micedramatically changed to a white color,reflecting excessive accumulation of fat inhepatocytes due to the lack of lipophagy.5We observed autophagic vesicles attachedto lipid droplets in WT livers using elec-tron microscopy, but autophagic vesicleswere rarely seen in Tak1DHEP livers.Although IkbkbDHEP mice havereduced autophagy induction,7 fastingdoes not cause a fatty liver appearance inthese mice (Seki, unpublished observa-tion). This suggests the existence ofanother mechanism in addition to autoph-agy that promotes hepatic lipid degrada-tion. mTORC1 is known to negativelyregulate peroxisome proliferator-activatedreceptor (PPAR) a-mediated functions.8Given the pronounced upregulation ofmTORC1 activity, hepatic PPARa activ-ity is suppressed in Tak1DHEP livers.Expression of PPARa-inducible genes(e.g., Acox1, Cpt1, and Hmgcs2) andPPARa-mediated b-oxidation weremarkedly suppressed by the loss of Tak1.5Suppression of lipophagy and PPARa-mediated b-oxidation promotes lipidaccumulation in the liver. Accordingly, ahigh-fat diet (HFD) challenge augmentedhepatic steatosis and inflammation inTak1DHEP mice as a result of the strongsuppression of autophagy and b-oxidationby Tak1-deficiency.5 Intriguingly, insulinresistance is comparable between WT andTak1DHEP mice with high fat diet (HFD)feeding, which suggests a dissociationbetween hepatosteatosis/ steatohepatitisand insulin resistance.Alternatively, the role of TAK1-medi-ated autophagy can be examined throughforced induction of autophagy by admin-istration of rapamycin to Tak1DHEP mice.In contrast to the severe fatty liver appear-ance in fasted Tak1DHEP mice, rapamycintreatment suppressed hepatic fat accumu-lation in these mice.5 We confirmed thatthe effect of rapamycin on the reductionof fat accumulation is largely dependenton autophagy using Atg5-silenced hepato-cytes.5 We also found decreased hepaticexpression of TAK1 in advanced fatty liverdisease, suggesting a mechanism wherebya decrease in TAK1 in advanced fatty liversuppresses autophagy and increasesmTORC1 activity, which further aug-ments hepatosteatosis and liver inflamma-tion and fibrosis, ultimately causingcarcinogenesis Figure 1.Since our previous study showing thatautophagy defects are associated with livertumor development,9 we have examinedthe role of autophagy defects in the devel-opment of liver fibrosis and tumorigenesisin our mouse model. Rapamycin-inducedautophagy significantly suppressed sponta-neous hepatocyte injury, liver fibrosis, andtumorigenesis in Tak1DHEP mice.5 Thissuggests that TAK1-mediated autophagyplays a role in preventing spontaneousliver fibrosis and cancer. The clinical rele-vance of TAK1 in human non-alcoholicsteatohepatitis (NASH) and hepatocarci-nogenesis is currently unknown, but onceits clinical relevance in human liver diseaseis understood, targeting TAK1 or TAK-1–mediated autophagy could be an impor-tant option for the prevention and treat-ment of human liver disease.Disclosure of Potential Conflicts of InterestNo potential conflicts of interest weredisclosedFundingThis work is supported by NIH grantsR01AA02172, R01DK085252, and P42ES010337.Figure 1. TAK1-mediated autophagy prevents hepatic steatosis and tumorigenesis. Upon nutritiondeprivation, TGF-b activated kinase 1 (TAK1) mediates autophagy through activation of AMP-acti-vated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin complex 1(mTORC1). TAK1 is also associated with induction of peroxisome proliferator-activated receptor(PPAR) a-mediated fatty acid oxidation (FAO) through suppression of mTORC1. Both autophagyand FAO contribute to lipid breakdown to prevent excessive lipid accumulation in hepatocytes.Autophagy prevents, and mTORC1 enhances, spontaneous tumorigenesis in the liver.e968507-2 Volume 1 Issue 4Molecular & Cellular OncologyReferences1. Roh YS, Song J, Seki E. TAK1 regulates hepatic cell sur-vival and carcinogenesis. J Gastroenterol 2014; 49:185-194; PMID:24443058; http://dx.doi.org/10.1007/s00535-013-0931-x2. Inokuchi S, Aoyama T, Miura K, Osterreicher CH,Kodama Y, Miyai K, Akira S, Brenner DA, Seki E. Dis-ruption of TAK1 in hepatocytes causes hepatic injury,inflammation, fibrosis, and carcinogenesis. Proc NatlAcad Sci U S A 2010; 107:844-849; PMID:20080763;http://dx.doi.org/10.1073/pnas.09097811073. Bettermann K, Vucur M, Haybaeck J, Koppe C, JanssenJ, Heymann F, Weber A, Weiskirchen R, Liedtke C,Gassler N, et al. TAK1 suppresses a NEMO-dependentbut NF-kappaB-independent pathway to liver cancer.Cancer Cell 2010; 17:481-496; PMID:20478530;http://dx.doi.org/10.1016/j.ccr.2010.03.0214. Herrero-Martin G, Hoyer-Hansen M, Garcia-Garcia C,Fumarola C, Farkas T, Lopez-Rivas A, Jaattela M.TAK1 activates AMPK-dependent cytoprotectiveautophagy in TRAIL-treated epithelial cells. EMBO J2009; 28:677-685; PMID:19197243; http://dx.doi.org/10.1038/emboj.2009.85. Inokuchi-Shimizu S, Park EJ, Roh YS, Yang L, Zhang B,Song J, Liang S, Pimienta M, Taniguchi K, Wu X, et al.TAK1-mediated autophagy and fatty acid oxidation pre-vent hepatosteatosis and tumorigenesis. J Clin Invest2014; 124:3566-3578; PMID:24983318; http://dx.doi.org/10.1172/JCI740686. Shin JH, Min SH, Kim SJ, Kim YI, Park J, Lee HK, YooOJ. TAK1 regulates autophagic cell death by suppressingthe phosphorylation of p70 S6 kinase 1. Sci Rep 2013;3:1561.7. Criollo A, Senovilla L, Authier H, Maiuri MC, Morselli E,Vitale I, Kepp O, Tasdemir E, Galluzzi L, Shen S, et al.The IKK complex contributes to the induction of autoph-agy. EMBO J 2010;29:619-631; PMID:19959994;http://dx.doi.org/10.1038/emboj.2009.3648. Sengupta S, Peterson TR, Laplante M, Oh S, SabatiniDM. mTORC1 controls fasting-induced ketogenesisand its modulation by ageing. Nature 2010;468:1100-1104; PMID:21179166; http://dx.doi.org/10.1038/nature095849. Ichimura Y, Waguri S, Sou YS, Kageyama S, HasegawaJ, Ishimura R, Saito T, Yang Y, Kouno T, Fukutomi T,et al. Phosphorylation of p62 activates the Keap1-Nrf2pathway during selective autophagy. Mol Cell2013;51:618-631; PMID:24011591; http://dx.doi.org/10.1016/j.molcel.2013.08.003www.landesbioscience.com e968507-3Molecular & Cellular Oncology

TAK1-dependent autophagy: A suppressor of fatty liver disease and hepatic oncogenesis

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TAK1-dependent autophagy: A suppressor of fatty liver disease and hepatic oncogenesis.

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