The Enhancement of Toxin-Induced Liver Fibrosis in Fatty Liver Disease. Ekihiro Seki, M.D.,Ph.D. University of California San Diego

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1 The Enhancement of Toxin-Induced Liver Fibrosis in Fatty Liver Disease Ekihiro Seki, M.D.,Ph.D. University of California San Diego

2 - A manufactured chemical. - Does not exist naturally. Carbon tetrachloride (CCl 4 ) - Clear liquid with a sweet odor that smells like chloroform. - Easily vaporizes. - High levels or continuous low dose exposure influence to liver, and cause hepatocyte injury, liver fibrosis and hepatocarcinogenesis. Trichloromethyl radical (Free radical) Lipid peroxidation Hepatotoxicity

3 Carbon tetrachloride (CCl 4 ) - Has been used for dry-cleaning, solvent, reagent in chemical synthesis, fire extinguisher fluid, and refrigerants. - The use and production of CCl 4 was declined in the mid 197s, but it has been diffusing into air, water and soil. It takes for several years to break down - In air of.1 ppb are common around the world. - In water or soil, ranging from 5 to over 1, ppb at 22% of the Superfund sites th and 5 th RANK (27 CERCLA and 211 ATSDR priority lists)

4 NAFLD Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of liver disease in the United States The prevalence of obesity and diabetes increases 6-7% of obese adults have NAFLD 3-4% of adults in the western world have NAFLD 15-2% of NAFLD patients progress to NASH According to a 28 estimation, NAFLD will be the leading cause for liver transplantation by 22.

5 Question: Does Fatty liver disease affects the sensitivity to toxin exposure? High fat diet Chronic Industrial Toxin Exposure Fatty Liver?

6 Activation of Stellate cells in Liver Fibrosis Carbon tetrachloride, HBV, HCV, NASH, Alcohol Cyp2E1 Hepatocyte Death TNF- TGF-? TGF- Activated Stellate cell

7 The Effect of Fatty Liver in Toxin-induced Liver Fibrosis 8x CCl 4 (.25ul/g BW) or corn oil LFD HFD HFD for 2M HFD for 1M 8x CCl 4 (.25ul/g BW) or corn oil

8 Serum ALT (U/L) HFD feeding enhances Toxin-induced Liver Injury LFD + Oil HFD + Oil LFD * HFD * 6 LFD + CCl 4 HFD + CCl Oil CCl 4 8 x CCl 4 (.25 ul/g BW)

9 Serum ALT (U/L) Tnf mrna [fold] Ccl2 mrna [fold] HFD feeding enhances Toxin-induced Liver Inflammation LFD HFD LFD HFD 12 * * 3 * 3 * * Oil CCl 4 Oil CCl 4 Oil CCl 4 8 x CCl 4 (.25 ul/g BW)

10 Sirius red staining area (%) HFD feeding enhances Toxin-induced Liver Fibrosis LFD HFD * * Oil CCl 4

11 Col1a1 mrna [fold] Acta2 mrna [fold] Timp1 mrna [fold] Tgfb1 mrna [fold] HFD feeding enhances Toxin-induced Liver Fibrosis LFD HFD * * * * * * * * Oil CCl Oil CCl 4 Oil CCl 4 Oil CCl

12 What is the Underlying Mechanism of Increased Sensitivity to CCl 4? High fat diet Chronic CCl 4 Exposure Fatty Liver 1. Increased sensitivity to hepatocyte death. 2. Increased capacity to produce cytokines. 3. Increased production of extracellular matrix. 4. Increased production of toxic metabolite from CCl 4.

13 Serine Rich region TGF- activated kinase 1 (TAK1) TAK1 is a 78-8 kda protein, which is encoded by the MAP3K7 gene. TAK1 is a serine/ threonine kinase, and belong to MAP3K family. Phosphorylation and ubiquitination of TAK1 are important for activation of TAK1 and its downstream molecules. TAK1 interacts with TAB1, TAB2 and TAB3 that regulate TAK1 full activation. TAK1 is activated in the signaling of TNF, IL-1, TLRs and TGF-. TAK1 regulates activation of NF- B, JNK, p38, AMPK and NLK. Catalytic domain P P 1 3 Thr Ser 36 Ser / P Lys Lys Thr Ub Ub P TAB1 TAB2/3

14 TAK1 Regulates NF- B and JNK Pathways, and also Regulates AMPK-Autophagy Pathway TNF TGF Metabolic stress (AMP/ATP, starvation) TAK1 TAK1 NEMO IKK NF- B JNK AP-1 AMPK mtorc1 autophagy Hepatocyte Death Hepatocyte Death

15 Tak1 mrna [fold] Tak1 mrna [fold] TAK1/ -actin [fold] Hepatic TAK1 expression is decreased in advanced fatty liver disease LFD ** LFD 8M-HFD TAK1 β-actin HFD ** WT Ob/Ob TAK1 β-actin LFD ** * HFD WT Ob/Ob WT Ob/Ob

16 Hepatic TAK1 expression is decreased in fatty liver with toxin exposure (2M) (2M)

17 Does Decreased TAK1 Expression Increase Sensitivity to CCl 4? High fat diet Chronic CCl 4 Exposure TAK1 Does Decreased TAK1 Play a Role? Fatty Liver

18 Generation of hepatocyte-specific TAK1-deleted mice Alb-Cre-Tg mice Tak1 flox/flox mice X Alb-promoter Cre-recombinase exon1 exon2 exon3 exon4 loxp loxp exon1 exon3 exon4 loxp TAK1 TAK1 Whole liver WT Tak1 HEP Hepatocytes WT Tak1 HEP TAK1 TAK1

19 Sirius red pos area (%) CCl 4 exposure augmentes liver fibrosis in Tak1 HEP mice WT-oil WT-CCl * * Tak1 HEP -oil Tak1 HEP -CCl 4 5 CCl injections (5-6 month old)

20 ALT (U/L) Col1a1 mrna [fold] Acta2 mrna [fold] Timp1 mrna [fold] TAK1 deficiency enhanced liver injury and fibrogenic response after chronic exposure to CCl * 4 2 CCl * * * * CCl CCl CCl

21 Why Does Decreased TAK1 Expression Increase Sensitivity to CCl 4 Exposure? 1.Sensitivity to TNF -induced hepatocyte death 2.Sensitivity to TGF -induced hepatocyte death 3.Autophagy in hepatocytes.

22 TAK1 -/- hepatocytes lack TNF -induced NF- B activation and are susceptible to cell death CCl 4 exposure inflammation TNF IL-1 TNF TNFR TAK1 NF- B Survival JNK Kupffer cells TGF DAMPs Hepatic stellate cells Caspase-3 Apoptosis Necrosis SMA TIMP1 Collagen Liver fibrosis Hepatocytes (Inokuchi et al 21, PNAS)

23 number of cell death (%) Caspase-3 activity (RFU/min) TAK1 -/- hepatocytes lack TNF -induced NF- B activation and are susceptible to cell death TNF- (min) NF- B pjnk JNK caspase-3 Cleaved caspase-3 WT (Inokuchi et al 21, PNAS) Tak1 HEP WT necrosis apoptosis WT ** TNF Tak1 HEP ** TNF Tak1 HEP

24 TAK1 -/- hepatocytes augment TGF -mediated Smad2/3 activation and are susceptible to cell death CCl 4 exposure inflammation TNF IL-1 TGF TGFbR TAK1 NF- B JNK Survival Kupffer cells TGF DAMPs Hepatic stellate cells Smad2/3/4 Caspase-3 Apoptosis Necrosis SMA TIMP1 Collagen Liver fibrosis Hepatocytes (Yang et al 213, Gastroenterology)

25 TUNEL-pos cells/hpf TAK1 -/- hepatocytes augment TGF -mediated Smad2/3 activation and are susceptible to cell death WT Tak1 HEP 3 * ** TGFβ(min) psmad2 Smad * * psmad3 1 Smad3 5 Cleaved Caspase3 Caspase3 TGFβ ng/ml WT Tak1 -/- Smad4 -/- Tak1 -/- Smad4 -/- (Yang et al 213, Gastroenterology)

26 Autophagy Autophagy is a process to degrade intracellular components (long-lived or aggregated proteins, lipids, and damaged organelles, such as mitochondria) in lysosomes to supply for energy generation for maintaining cellular homeostasis. Cell death, Cancer, Fatty Liver, Type II Diabetes, Innate Immune Systems, Aging, Infectious Disease, Toxin exposure, Fibrosis.

27 LC3B aggregates/ cell N.D. % LD with AV Fasted Fed WT Autophagy is suppressed in TAK1 HEP mice Tak1 hep Fed Fasted Fed Fasted LC3B IHC Electron Microscope WT Tak1 hep WT Tak1 hep p-s6 p62 LC3B-I LC3B-II -actin Fasted Fed Starvation Hepatocyte Death TAK1 AMPK mtorc1 Autophagy WT ** Fed Tak1 hep WT Tak1 hep ** ** 5 * ** Fasted Fed Fasted (Inokuchi-Shimizu et al 214, J Clin Invest)

28 Ratio (LC3B-GFP-II/I) TAK1 -/- -LC3B GFP WT-LC3B GFP LC3B-GFP (dots/cell) Autophagic LC3B aggregation is suppressed in TAK1 -/- hepatocytes medium starvation 6 ** ** WT Tak1 -/- medium WT Tak1 -/- starvation GFP-LC3B-I GFP-LC3B-II p62 -actin WT Tak1 -/- starvation starvation 3 ** 2 1 starvation WT Tak1 -/-

29 Starvation-induced AMPK activation is inhibited in TAK1 -/- hepatocytes TAK1 plkb1 WT Tak1 -/- starvation starvation 2h 6h 2h 6h Starvation TAK1 LKB1 pampk AMPK praptor Raptor pulk1 ULK1 -actin P P LKB1 AMPK P P Raptor ULK1 mtor Autophagy mtorc1 LC3B p62

30 Rapamycin Restores Autophagy in TAK1 -/- Hepatocytes WT Starvation WT TAK1 -/- rapa TAK1 Tak1 GFP-LC3B-I GFP-LC3B-II p62 ps6 TAK1 -/- P LKB1 AMPK Raptor P P T-S6 -actin (Inokuchi-Shimizu et al 214, J Clin Invest) mtor Autophagy S6K Rapa P S6

31 TUNEL pos cells (/x1 filed) ALT (U/L) Rapamycin Suppresses Liver Injury in Tak1 HEP mice 6 2 * * rapamycin rapamycin WT TAK1 HEP WT TAK1 HEP (Inokuchi-Shimizu et al 214, J Clin Invest)

32 Sirius Red pos Area (%) Rapamycin Suppresses Liver Fibrosis in Tak1 HEP mice Tak1 HEP mice 8 * 6 4 Vehicle rapamycin Injection of 5mg/kgBW rapamycin 2 times/week from 28 to 36 weeks 2 Vehicle rapa (Inokuchi-Shimizu et al 214, J Clin Invest)

33 The enhancement of toxin-induced liver fibrosis in fatty liver disease High fat diet Carbon Tetrachloride Exposure Steatotic Hepatocytes TAK1 NF-κB Smad2/3 Autophagy Hepatocyte Death Stellate Cell Activation

34 Fatty liver disease changes the sensitivity to toxin exposure that enhances liver fibrosis High fat diet Chronic Industrial Toxin Exposure Fatty Liver Liver Cirrhosis

35 Acknowledgement UC San Diego Superfund Research Center Ekihiro Seki MD, PhD (Project5) David A. Brenner MD (Co-leader) Yoon Seok Roh DVM,PhD Shuang Liang PhD Hiroshi Matsushita MD, PhD Sayaka Inokuchi-Shimuzu MD,PhD Ling Yang MD,PhD Bi Zhang Jingyi Song Robert Tukey PhD (Director) Michael Karin PhD (Project 1) Koji Taniguchi MD,PhD XieFeng Wu PhD Mark Ellisman PhD (Core) Mason Mackey

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