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Pflügers Archiv - European Journal of Physiology

, Volume 465, Issue 9, pp 1303–1316 | Cite as

Dietary capsaicin prevents nonalcoholic fatty liver disease through transient receptor potential vanilloid 1-mediated peroxisome proliferator-activated receptor δ activation

  • Qiang Li
  • Li Li
  • Fei Wang
  • Jian Chen
  • Yu Zhao
  • Peijian Wang
  • Bernd Nilius
  • Daoyan LiuEmail author
  • Zhiming ZhuEmail author
Molecular and Cellular Mechanisms of Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid deposition and coincides often with cardiometabolic diseases. Several dietary factors attenuate NAFLD. Here, we report beneficial effects of chronic dietary capsaicin intake on NAFLD which is mediated by the transient receptor potential vanilloid 1 (TRPV1) activation. The results showed that TRPV1 activation by capsaicin reduced free fatty acids (FFAs) induced the intracellular lipid droplets in HepG2 cells and prevented fatty liver in vivo. Chronic dietary capsaicin promoted lipolysis by increasing hepatic phosphorylated hormone-sensitive lipase (phospho-HSL), carnitine palmitoyltransferase 1 (CPT1), and peroxisome proliferator-activated receptor δ (PPARδ) in wild-type (WT) mice. This effect was absent in TRPV1−/− mice. Dietary capsaicin did not affect lipogenesis, as indicated by the detection of hepatic fatty acid synthase (FAS), sterol regulatory element-binding protein-1 (SREBP-1), PPARα, and liver X receptor (LXR) in mice. Importantly, TRPV1 causes PPARδ activation which significantly increased the expression of autophagy-related proteins, such as light chain 3 (LC3)II, Beclin1, Atg5, and Atg7 in HepG2 cells. In the in vivo study, TRPV1 activation by dietary capsaicin enhanced hepatic PPARδ and autophagy-related proteins and reduced hepatic enzymes and inflammatory factor in WT but not TRPV1−/− mice. TRPV1 activation by dietary capsaicin prevents NAFLD through PPARδ-dependent autophagy enhancement in mice. Dietary capsaicin may represent a beneficial intervention in populations at high risk for NAFLD.

Keywords

Autophagy Lipolysis NAFLD PPARδ TRPV1 

Abbreviations

NAFLD

Nonalcoholic fatty liver disease

WT

Wild-type

TRPV1

Transient receptor potential vanilloid 1

TRPV1−/−

TRPV1 knockout

FFAs

Free fatty acids

HSL

Hormone-sensitive lipase

CPT1

Carnitine palmitoyltransferase 1

ATGL

Adipose triglyceride lipase

PPAR

Peroxisome proliferator-activated receptor

FAS

Fatty acid synthase

SREBP-1

Sterol regulatory element-binding protein-1

LXR

Liver X receptor

LC3

Light chain 3

LDs

Lipid droplets

DMEM

Dulbecco's modified Eagle's medium

FBS

Fetal bovine serum

CAP

Capsaicin

CAPZ

Capsazepine

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

TNFα

Tumor necrosis factor α

Notes

Acknowledgments

We thank Quan Chen (The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China) for presenting GFP-LC3 plasmid. We thank Tingbin Cao and Lijuan Wang (Chongqing Institute of Hypertension, China) for technical assistance. We thank Bin Tan (Institute of Pediatrics, Chongqing Medical Science University) for immunofluorescence images. We thank Yu Huang (Chinese University of Hong Kong, China) for critical review of the manuscript.

Sources of Funding

The National Basic Research Program of China (2012CB517805 and 2012CB517806 and 2011CB503902) and the National Natural Science Foundation of China (30890042).

Supplementary material

424_2013_1274_MOESM1_ESM.doc (1.9 mb)
ESM 1 (DOC 1966 kb)

References

  1. 1.
    Alisi A, Feldstein AE, Villani A, Raponi M, Nobili V (2012) Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach. Nat Rev Gastroenterol Hepatol 9:152–161PubMedCrossRefGoogle Scholar
  2. 2.
    Amir M, Czaja MJ (2011) Autophagy in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 5:159–166PubMedCrossRefGoogle Scholar
  3. 3.
    Argo CK, Loria P, Caldwell SH, Lonardo A (2008) Statins in liver disease: a molehill, an iceberg, or neither? Hepatology 48:662–669PubMedCrossRefGoogle Scholar
  4. 4.
    Bellentani S, Dalle Grave R, Suppini A, Marchesini G (2008) Behavior therapy for nonalcoholic fatty liver disease: the need for a multidisciplinary approach. Hepatology 47:746–754PubMedCrossRefGoogle Scholar
  5. 5.
    Chamulitrat W, Burhenne J, Rehlen T, Pathil A, Stremmel W (2009) Bile salt-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide as a hepatoprotective agent. Hepatology 50:143–154PubMedCrossRefGoogle Scholar
  6. 6.
    Ducheix S, Lobaccaro JM, Martin PG, Guillou H (2011) Liver X Receptor: an oxysterol sensor and a major player in the control of lipogenesis. Chem Phys Lipids 164:500–514PubMedCrossRefGoogle Scholar
  7. 7.
    El-Badry AM, Moritz W, Contaldo C, Tian Y, Graf R, Clavien PA (2007) Prevention of reperfusion injury and microcirculatory failure in macrosteatotic mouse liver by omega-3 fatty acids. Hepatology 45:855–863PubMedCrossRefGoogle Scholar
  8. 8.
    Fabbrini E, Sullivan S, Klein S (2010) Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 51:679–689PubMedCrossRefGoogle Scholar
  9. 9.
    Farrell GC, Larter CZ (2006) Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43:S99–S112PubMedCrossRefGoogle Scholar
  10. 10.
    Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, Lippincott-Schwartz J (2010) Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141:656–667PubMedCrossRefGoogle Scholar
  11. 11.
    Harrison SA (2010) Thiazolidinedione therapy for nonalcoholic steatohepatitis: go, stop, or proceed with caution? Hepatology 51:366–369PubMedCrossRefGoogle Scholar
  12. 12.
    He H, Yang D, Ma L, Luo Z, Ma S, Feng X, Cao T, Yan Z, Liu D, Tepel M, Zhu Z (2010) Telmisartan prevents weight gain and obesity through activation of peroxisome proliferator-activated receptor-delta-dependent pathways. Hypertension 55:869–879PubMedCrossRefGoogle Scholar
  13. 13.
    Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA (2012) Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482:179–185PubMedGoogle Scholar
  14. 14.
    Holzer P (2011) Transient receptor potential (TRP) channels as drug targets for diseases of the digestive system. Pharmacol Ther 131:142–170PubMedCrossRefGoogle Scholar
  15. 15.
    Jensen-Urstad AP, Semenkovich CF (2012) Fatty acid synthase and liver triglyceride metabolism: housekeeper or messenger? Biochim Biophys Acta 1821:747–753PubMedCrossRefGoogle Scholar
  16. 16.
    Jiang M, Fernandez S, Jerome WG, He Y, Yu X, Cai H, Boone B, Yi Y, Magnuson MA, Roy-Burman P, Matusik RJ, Shappell SB, Hayward SW (2010) Disruption of PPARgamma signaling results in mouse prostatic intraepithelial neoplasia involving active autophagy. Cell Death Differ 17:469–481PubMedCrossRefGoogle Scholar
  17. 17.
    Jiang M, Jerome WG, Hayward SW (2010) Autophagy in nuclear receptor PPARgamma-deficient mouse prostatic carcinogenesis. Autophagy 6:175–176PubMedCrossRefGoogle Scholar
  18. 18.
    Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Unalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR (2011) Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 305:1659–1668PubMedCrossRefGoogle Scholar
  19. 19.
    Li L, Chen J, Ni Y, Feng X, Zhao Z, Wang P, Sun J, Yu H, Yan Z, Liu D, Nilius B, Zhu Z (2012) TRPV1 activation prevents nonalcoholic fatty liver through UCP2 upregulation in mice. Pflugers Arch 463:727–732PubMedCrossRefGoogle Scholar
  20. 20.
    Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, Ma Q, Zhu C, Wang R, Qi W, Huang L, Xue P, Li B, Wang X, Jin H, Wang J, Yang F, Liu P, Zhu Y, Sui S, Chen Q (2012) Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol 14:177–185PubMedCrossRefGoogle Scholar
  21. 21.
    Malavazos AE, Gobbo G, Zelaschi RF, Cereda E (2010) Lifestyle intervention and fatty liver disease: the importance of both disrupting inflammation and reducing visceral fat. Hepatology 51:1091–1092PubMedGoogle Scholar
  22. 22.
    Miao X, Liu G, Xu X, Xie C, Sun F, Yang Y, Zhang T, Hua S, Fan W, Li Q, Huang S, Wang Q, Zhong D (2008) High expression of vanilloid receptor-1 is associated with better prognosis of patients with hepatocellular carcinoma. Cancer Genet Cytogenet 186:25–32PubMedCrossRefGoogle Scholar
  23. 23.
    Musso G, Gambino R, Cassader M (2010) Emerging molecular targets for the treatment of nonalcoholic fatty liver disease. Annu Rev Med 61:375–392PubMedCrossRefGoogle Scholar
  24. 24.
    Nagasawa T, Inada Y, Nakano S, Tamura T, Takahashi T, Maruyama K, Yamazaki Y, Kuroda J, Shibata N (2006) Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur J Pharmacol 536:182–191PubMedCrossRefGoogle Scholar
  25. 25.
    Nilius B, Owsianik G (2011) The transient receptor potential family of ion channels. Genome Biol 12:218PubMedCrossRefGoogle Scholar
  26. 26.
    Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient receptor potential cation channels in disease. Physiol Rev 87:165–217PubMedCrossRefGoogle Scholar
  27. 27.
    Nilius B, Vennekens R, Owsianik G (2008) Vanilloid transient receptor potential cation channels: an overview. Curr Pharm Des 14:18–31PubMedCrossRefGoogle Scholar
  28. 28.
    Oh SH, Kim YS, Lim SC, Hou YF, Chang IY, You HJ (2008) Dihydrocapsaicin (DHC), a saturated structural analog of capsaicin, induces autophagy in human cancer cells in a catalase-regulated manner. Autophagy 4:1009–1019PubMedGoogle Scholar
  29. 29.
    Ost A, Svensson K, Ruishalme I, Brannmark C, Franck N, Krook H, Sandstrom P, Kjolhede P, Stralfors P (2010) Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Mol Med 16:235–246PubMedCrossRefGoogle Scholar
  30. 30.
    Park HJ, DiNatale DA, Chung MY, Park YK, Lee JY, Koo SI, O'Connor M, Manautou JE, Bruno RS (2011) Green tea extract attenuates hepatic steatosis by decreasing adipose lipogenesis and enhancing hepatic antioxidant defenses in ob/ob mice. J Nutr Biochem 22:393–400PubMedCrossRefGoogle Scholar
  31. 31.
    Qin X, Xie X, Fan Y, Tian J, Guan Y, Wang X, Zhu Y, Wang N (2008) Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology 48:432–441PubMedCrossRefGoogle Scholar
  32. 32.
    Rautou PE, Mansouri A, Lebrec D, Durand F, Valla D, Moreau R (2010) Autophagy in liver diseases. J Hepatol 53:1123–1134PubMedCrossRefGoogle Scholar
  33. 33.
    Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA (2011) GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS One 6:e25269PubMedCrossRefGoogle Scholar
  34. 34.
    Shin HW, Kim D, Lee Y, Yoo HS, Lee BJ, Kim JS, Jang S, Lim H, Oh S (2009) Alteration of sphingolipid metabolism and pSTAT3 expression by dietary cholesterol in the gallbladder of hamsters. Arch Pharm Res 32:1253–1262PubMedCrossRefGoogle Scholar
  35. 35.
    Siemens J, Zhou S, Piskorowski R, Nikai T, Lumpkin EA, Basbaum AI, King D, Julius D (2006) Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature 444:208–212PubMedCrossRefGoogle Scholar
  36. 36.
    Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135PubMedCrossRefGoogle Scholar
  37. 37.
    Tailleux A, Wouters K, Staels B (2012) Roles of PPARs in NAFLD: potential therapeutic targets. Biochim Biophys Acta 1821:809–818PubMedCrossRefGoogle Scholar
  38. 38.
    Widhalm K, Ghods E (2010) Nonalcoholic fatty liver disease: a challenge for pediatricians. Int J Obes (Lond) 34:1451–1467CrossRefGoogle Scholar
  39. 39.
    Wu X, Zhang L, Gurley E, Studer E, Shang J, Wang T, Wang C, Yan M, Jiang Z, Hylemon PB, Sanyal AJ, Pandak WM Jr, Zhou H (2008) Prevention of free fatty acid-induced hepatic lipotoxicity by 18beta-glycyrrhetinic acid through lysosomal and mitochondrial pathways. Hepatology 47:1905–1915PubMedCrossRefGoogle Scholar
  40. 40.
    Yang D, Luo Z, Ma S, Wong WT, Ma L, Zhong J, He H, Zhao Z, Cao T, Yan Z, Liu D, Arendshorst WJ, Huang Y, Tepel M, Zhu Z (2010) Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension. Cell Metab 12:130–141PubMedCrossRefGoogle Scholar
  41. 41.
    Yang L, Li P, Fu S, Calay ES, Hotamisligil GS (2010) Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab 11:467–478PubMedCrossRefGoogle Scholar
  42. 42.
    York LW, Puthalapattu S, Wu GY (2009) Nonalcoholic fatty liver disease and low-carbohydrate diets. Annu Rev Nutr 29:365–379PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang LL, Yan Liu D, Ma LQ, Luo ZD, Cao TB, Zhong J, Yan ZC, Wang LJ, Zhao ZG, Zhu SJ, Schrader M, Thilo F, Zhu ZM, Tepel M (2007) Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ Res 100:1063–1070PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Qiang Li
    • 1
  • Li Li
    • 1
  • Fei Wang
    • 1
  • Jian Chen
    • 1
  • Yu Zhao
    • 1
  • Peijian Wang
    • 1
  • Bernd Nilius
    • 2
  • Daoyan Liu
    • 1
    Email author
  • Zhiming Zhu
    • 1
    Email author
  1. 1.Center for Hypertension and Metabolic Diseases, Department of Hypertension and EndocrinologyDaping Hospital, Third Military Medical University, Chongqing Institute of HypertensionChongqingChina
  2. 2.Department of Cell Molecular Medicine, Laboratory Ion Channel ResearchCampus Gasthuisberg, KU LeuvenLeuvenBelgium

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