Browse > Article
http://dx.doi.org/10.5352/JLS.2019.29.9.964

Effects of Piperine on Insulin Resistance and Lipid Accumulation in Palmitate-treated HepG2 Cells  

Jung, Hee Jin (Longevity Life Science and Technology Institutes, Pusan National University)
Bang, EunJin (Department of Pharmacy, College of Pharmacy, Pusan National University)
Jeong, Seong Ho (Department of Pharmacy, College of Pharmacy, Pusan National University)
Kim, Byeong Moo (Department of Pharmacy, College of Pharmacy, Pusan National University)
Chung, Hae Young (Longevity Life Science and Technology Institutes, Pusan National University)
Publication Information
Journal of Life Science / v.29, no.9, 2019 , pp. 964-971 More about this Journal
Abstract
Hepatic lipid accumulation and insulin resistance increases in patients with non-alcoholic fatty liver disease. Piperine is a major compound found in black pepper (Piper nigrum) and long pepper (P. longum). Piperine has been used in fine chemical for its anti-cancer, anti-obesity, anti-diabetic, anti-inflammatory and anti-oxidant properties. However, the signaling-based mechanism of piperine and its role as an inhibitor of lipogenesis and insulin resistance in human hepatocyte cells remains ill-defined. In the present study, we explored the effects of piperine on lipid accumulation and insulin resistance, and explored the potential underlying molecular mechanisms in palmitate-treated HepG2 cells. Piperine treatment resulted in a significant reduction of triglyceride content. Furthermore, piperine treatment decreased palmitate-treated intracellular lipid deposition by inhibiting the lipogenic target genes, sterol-regulatory-element-binding protein 1c (SREBP-1c) and fatty acid synthase (FAS); whereas the expression of carnitine palmitoyl transferase (CPT-1) and phosphorylation of acetyl coenzyme A carboxylase (ACC) gene involved in fatty acid oxidation was increased. Moreover, piperine also inhibited the phosphorylation of insulin receptor substrate (IRS)-1 (Ser307). Piperine treatment modulated palmitate-treated lipid accumulation and insulin resistance in HepG2 cells with concomitant reduction of lipogenic target genes, such as SREBP-1 and FAS, and induction of CPT-1-ACC and phosphorylation of IRS-1 (Tyr632)-Akt pathways. Therefore, piperine represents a promising treatment for the prevention of lipid accumulation and insulin resistance.
Keywords
Insulin resistance; lipid accumulation; palmitate; piperine;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Guillet-Deniau, I., Pichard, A. L., Koné, A., Esnous, C., Nieruchalski, M., Girard, J. and Prip-Buus, C. 2004. Glucose induces de novo lipogenesis in rat muscle satellite cells through a sterol-regulatory-element-binding-protein-1c-dependent pathway. J. Cell Sci. 117, 1937-1944.   DOI
2 Habib, A., Creminon, C., Frobert, Y., Grassi, J., Pradelles, P. and Maclouf, J. 1993. Demonstration of an inducible cyclooxygenase in human endothelial cells using antibodies raised against the carboxyl-terminal region of the cyclooxygenase-2. J. Biol. Chem. 268, 23448-23454.   DOI
3 Ishii, M., Maeda, A., Tani, S. and Akagawa, M. 2015. Palmitate induces insulin resistance in human HepG2 hepatocytes by enhancing ubiquitination and proteasomal degradation of key insulin signaling molecules. Arch. Biochem. Biophys. 566, 26-35.   DOI
4 Jensen-Urstad, A. P. and Semenkovich, C. F. 2012. Fatty acid synthase and liver triglyceride metabolism: housekeeper or messenger? Biochim. Biophys. Acta 1821, 747-753.   DOI
5 Jung, T. W., Choi, H. Y., Lee, S. Y., Hong, H. C., Yang, S. J., Yoo, H. J., Youn, B. S., Baik, S. H. and Choi, K. M. 2013. Salsalate and adiponectin improve palmitate-induced insulin resistance via inhibition of selenoprotein P through the AMPK- FOXO1alpha pathway. PloS One 8, e66529.   DOI
6 Jwa, H., Choi, Y., Park, U. H., Um, S. J., Yoon, S. K. and Park, T. 2012. Piperine, an $LXR{\alpha}$ antagonist, protects against hepatic steatosis and improves insulin signaling in mice fed a high-fat diet. Biochem. Pharmacol. 84, 1501-1510.   DOI
7 Li, J., Ding, L., Song, B., Xiao, X., Qi, M., Yang, Q., Yang, Q., Tang, X., Wang, Z. and Yang, L. 2016. Emodin improves lipid and glucose metabolism in high fat diet-induced obese mice through regulating SREBP pathway. Eur. J. Pharmacol. 770, 99-109.   DOI
8 Lin, Y., Xu, J., Liao, H., Li, L. and Pan, L. 2014. Piperine induces apoptosis of lung cancer A549 cells via p53-dependent mitochondrial signaling pathway. Tumour Biol. 35, 3305-3310.   DOI
9 Yu, X. X., Murray, S. F., Pandey, S. K., Booten, S. L., Bao, D., Song, X. Z., Kelly, S., Chen, S., McKay, R., Monia, B. P. and Bhanot, S. 2005. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology 42, 362-371.   DOI
10 Lin, W. C., Shih, P. H., Wang, W., Wu, C. H., Hsia, S. M., Wang, H. J., Hwang, P. A., Wang, C. Y., Chen, S. H. and Kuo, Y. T. 2015. Inhibitory effects of high stability fucoxanthin on palmitic acid-induced lipid accumulation in human adipose-derived stem cells through modulation of long non-coding RNA. Food Funct. 6, 2215-2223.   DOI
11 Nakamura, S., Takamura, T., Matsuzawa-Nagata, N., Takayama, H., Misu, H., Noda, H., Nabemoto, S., Kurita, S., Ota, T., Ando, H., Miyamoto, K. and Kaneko, S. 2009. Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. J. Biol. Chem. 284, 14809-14818.   DOI
12 Zhang, Y., Liu, X., Han, L., Gao, X., Liu, E. and Wang, T. 2013. Regulation of lipid and glucose homeostasis by mango tree leaf extract is mediated by AMPK and PI3K/AKT signaling pathways. Food Chem. 141, 2896-2905.   DOI
13 Michelotti, G. A., Machado, M. V. and Diehl, A. M. 2013. NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10, 656-665.   DOI
14 Mittal, R. and Gupta, R. L. 2000. In vitro antioxidant activity of piperine. Method. Find. Exp.Clin. Pharmacol. 22, 271-274.   DOI
15 Nguyen, M. T., Satoh, H., Favelyukis, S., Babendure, J. L., Imamura, T., Sbodio, J. I., Zalevsky, J., Dahiyat, B. I., Chi, N. W. and Olefsky, J. M. 2005. JNK and tumor necrosis factor- alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J. Biol. Chem. 280, 35361-35371.   DOI
16 Park, J. Y., Kim, Y., Im, J. A. and Lee, H. 2015. Oligonol suppresses lipid accumulation and improves insulin resistance in a palmitate-induced in HepG2 hepatocytes as a cellular steatosis model. BMC Complement Altern. Med. 15, 185.   DOI
17 Rauscher, F. M., Sanders, R. A. and Watkins, J. B. 3rd. 2000. Effects of piperine on antioxidant pathways in tissues from normal and streptozotocin-induced diabetic rats. J. Biochem. Mol. Toxicol. 14, 329-334.   DOI
18 Yokoyama, K., Tatsumi, Y., Hayashi, K., Goto, H., Ishikawa, T. and Wakusawa, S. 2017. Effects of ursodeoxycholic acid and insulin on palmitate-induced ROS production and down-regulation of PI3K/Akt signaling activity. Biol. Pharm. Bull. 40, 2001-2004.   DOI
19 McGarry, J. D. and Brown, N. F. 1997. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur. J. Biochem. 244, 1-14.   DOI
20 Yang, M., Wei, D., Mo, C., Zhang, J., Wang, X., Han, X., Wang, Z. and Xiao, H. 2013. Saturated fatty acid palmitate- induced insulin resistance is accompanied with myotube loss and the impaired expression of health benefit myokine genes in C2C12 myotubes. Lipids Health Dis. 12, 104.   DOI
21 Shimano, H., Yahagi, N., Amemiya-Kudo, M., Hasty, A. H., Osuga, J., Tamura, Y., Shionoiri, F., Iizuka, Y., Ohashi, K., Harada, K., Gotoda, T., Ishibashi, S. and Yamada, N. 1999. Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J. Biol. Chem. 274, 35832-35839.   DOI
22 Reddy, J. K. and Rao, M. S. 2006. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G852-858.   DOI
23 Saltiel, A. R. and Kahn, C. R. 2001. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799-806.   DOI
24 Selvendiran, K., Banu, S. M. and Sakthisekaran, D. 2004. Protective effect of piperine on benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Clin. Chim. Acta 350, 73-78.   DOI
25 Srinivasan, K. 2007. Black pepper and its pungent principle- piperine: a review of diverse physiological effects. Crit. Rev. Food Sci. Nutr. 47, 735-748.   DOI
26 Umar, S., Golam Sarwar, A. H., Umar, K., Ahmad, N., Sajad, M., Ahmad, S., Katiyar, C. K. and Khan, H. A. 2013. Piperine ameliorates oxidative stress, inflammation and histological outcome in collagen induced arthritis. Cell Immunol. 284, 51-59.   DOI
27 Wang, D., Tian, M., Qi, Y., Chen, G., Xu, L., Zou, X., Wang, K., Dong, H. and Lu, F. 2015. Jinlida granule inhibits palmitic acid induced-intracellular lipid accumulation and enhances autophagy in NIT-1 pancreatic beta cells through AMPK activation. J. Ethnopharmacol. 161, 99-107.   DOI
28 Atal, S., Agrawal, R. P., Vyas, S., Phadnis, P. and Rai, N. 2012. Evaluation of the effect of piperine per se on blood glucose level in alloxan-induced diabetic mice. Acta. Pol. Pharm. 69, 965-969.
29 Wolfgang, M. J. and Lane, M. D. 2011. Hypothalamic malonyl- CoA and CPT1c in the treatment of obesity. FEBS J. 278, 552-558.   DOI
30 Arcaro, C. A., Gutierres, V. O., Assis, R. P., Moreira, T. F., Costa, P. I., Baviera, A. M. and Brunetti, I. L. 2014. Piperine, a natural bioenhancer, nullifies the antidiabetic and antioxidant activities of curcumin in streptozotocin-diabetic rats. PloS One 9, e113993.   DOI
31 Adrian, L., Lenski, M., Todter, K., Heeren, J., Bohm, M. and Laufs, U. 2017. AMPK prevents palmitic acid-induced apoptosis and lipid accumulation in cardiomyocytes. Lipids 52, 737-750.   DOI
32 Ahmed, M. H. and Byrne, C. D. 2007. Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease (NAFLD). Drug Discov. Today 12, 740-747.   DOI
33 Atshaves, B. P., Storey, S. M., Petrescu, A., Greenberg, C. C., Lyuksyutova, O. I., Smith, R. 3rd. and Schroeder, F. 2002. Expression of fatty acid binding proteins inhibits lipid accumulation and alters toxicity in L cell fibroblasts. Am. J. Physiol. Cell Physiol. 283, C688-703.   DOI
34 Bhala, N., Younes, R. and Bugianesi, E. 2013. Epidemiology and natural history of patients with NAFLD. Curr. Pharm. Des. 19, 5169-5176.   DOI
35 Dihingia, A., Bordoloi, J., Dutta, P., Kalita J. and Manna, P. 2018. Hexane-isopropanolic extract of tungrymbai, a north-east indian fermented soybean food prevents hepatic steatosis via regulating AMPK-mediated SREBP/FAS/ ACC/HMGCR and $PPAR{\alpha}$/CPT1A/UCP2 pathways. Sci. Rep. 8, 10021.   DOI
36 Boizard, M., Le Liepvre, X., Lemarchand, P., Foufelle, F., Ferre, P. and Dugail, I. 1998. Obesity-related overexpression of fatty-acid synthase gene in adipose tissue involves sterol regulatory element-binding protein transcription factors. J. Biol. Chem. 273, 29164-29171.   DOI
37 Brownsey, R. W., Boone, A. N., Elliott, J. E., Kulpa, J. E. and Lee, W. M. 2006. Regulation of acetyl-CoA carboxylase. Biochem. Soc. Trans. 34, 223-227.   DOI
38 Chavez, J. A. and Summers, S. A. 2003. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch. Biochem. Biophys. 419, 101-109.   DOI
39 Choi, S., Choi, Y., Choi, Y., Kim, S., Jang, J. and Park, T. 2013. Piperine reverses high fat diet-induced hepatic steatosis and insulin resistance in mice. Food Chem. 141, 3627-3635.   DOI
40 Copps, K. D. and White, M. F. 2012. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55, 2565-2582.   DOI
41 Diwan, V., Poudyal, H. and Brown, L. 2013. Piperine attenuates cardiovascular, liver and metabolic changes in high carbohydrate, high fat-fed rats. Cell Biochem. Biophys. 67, 297-304.   DOI
42 Gomez-Lechon, M. J., Donato, M. T., Martinez-Romero, A., Jimenez, N., Castell, J. V. and O'Connor, J. E. 2007. A human hepatocellular in vitro model to investigate steatosis. Chem. Biol. Interact. 165, 106-116.   DOI
43 Doucette, C. D., Hilchie, A. L., Liwski, R. and Hoskin, D. W. 2013. Piperine, a dietary phytochemical, inhibits angiogenesis. J. Nutr. Biochem. 24, 231-239.   DOI
44 Gao, D. and Li, Y. 2017. Identification and preliminary structure- activity relationships of 1-indanone derivatives as novel indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors. Bioorg. Med. Chem. 25, 3780-3791.   DOI
45 Goldstein, J. L., DeBose-Boyd, R. A. and Brown, M. S. 2006. Protein sensors for membrane sterols. Cell 124, 35-46.   DOI