Hydrogen sulfide inhibits PCSK9 expression through the PI3K/Akt‑SREBP‑2 signaling pathway to influence lipid metabolism in HepG2 cells

Xiao,Jun; Bai,Xue‑Qin; Liao,Ling; Zhou,Min; Peng,Juan; Xiang,Qiong; Ren,Zhong; Wen,Hong‑Yan; Jiang,Zhi‑Sheng; Tang,Zhi‑Han; Wang,Mei‑Mei; Liu,Lu‑Shan

doi:10.3892/ijmm.2019.4118

Hydrogen sulfide inhibits PCSK9 expression through the PI3K/Akt‑SREBP‑2 signaling pathway to influence lipid metabolism in HepG2 cells

Authors:
- Jun Xiao
- Xue‑Qin Bai
- Ling Liao
- Min Zhou
- Juan Peng
- Qiong Xiang
- Zhong Ren
- Hong‑Yan Wen
- Zhi‑Sheng Jiang
- Zhi‑Han Tang
- Mei‑Mei Wang
- Lu‑Shan Liu
View Affiliations

Affiliations: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China, Medical College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China, Department of Pediatrics, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
Published online on: March 1, 2019 https://doi.org/10.3892/ijmm.2019.4118
Pages: 2055-2063
Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule that plays important roles in the cardiovascular system. In our previous studies, we demonstrated that H2S regulates lipid metabolism. In the present study, we aimed to explore the mechanisms through which H2S regulates lipid metabolism in HepG2 cells in vitro. Treatment of the HepG2 cells with H2S inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and increased the level of low‑density lipoprotein receptor (LDLR) in a time‑ and dose‑dependent manner. The knockdown of PCSK9 by siRNA effectively increased the levels of LDLR and 1,1'‑dioctadecyl‑3,3,3',3'‑tetramethyl‑indocarbocyanine perchlorate‑labeled LDL (DiI‑LDL) uptake in the H2S‑treated HepG2 cells. Furthermore, the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt)‑sterol regulatory element binding proteins 2 (SREBP‑2) signaling pathway was confirmed to be involved in H2S‑regulated PCSK9 expression. Notably, the HepG2 cells were incubated with 30% serum and DiI‑LDL for 24 h, and the results revealed that H2S increased lipid uptake, but caused no increase in lipid accumulation. On the whole, the findings of this study demonstrate that H2S is involved in the regulation of lipid metabolism in HepG2 cells through the regulation of the expression of PCSK9 via the PI3K/Akt‑SREBP‑2 signaling pathway. To the very best of our knowledge, this study is the first to report that H2S can regulate the expression of PCSK9.

View Figures

View References

1	Li D, Xiong Q, Peng J, Hu B, Li W, Zhu Y and Shen X: Hydrogen Sulfide upregulates the expression of ATP-binding cassette transporter A1 via promoting nuclear translocation of PPARα. Int J Mol Sci. 17:E6352016. View Article : Google Scholar
2	Wu D, Zheng N, Qi K, Cheng H, Sun Z, Gao B, Zhang Y, Pang W, Huangfu C, Ji S, et al: Exogenous hydrogen sulfide mitigates the fatty liver in obese mice through improving lipid metabolism and antioxidant potential. Med Gas Res. 5:12015. View Article : Google Scholar : PubMed/NCBI
3	Li H, Mani S, Wu L, Fu M, Shuang T, Xu C and Wang R: The interaction of estrogen and CSE/H₂S pathway in the development of atherosclerosis. Am J Physiol Heart Circ Physiol. 312:H406–H414. 2017. View Article : Google Scholar
4	Gao L, Xu Z, Yin Z, Chen K, Wang C and Zhang H: Association of hydrogen sulfide with alterations of monocyte chemokine receptors, CCR2 and CX3CR1 in patients with coronary artery disease. Inflamm Res. 64:627–635. 2015. View Article : Google Scholar : PubMed/NCBI
5	Lin XL, Xiao LL, Tang ZH, Jiang ZS and Liu MH: Role of PCSK9 in lipid metabolism and atherosclerosis. Biomed Pharmacother. 104:36–44. 2018. View Article : Google Scholar : PubMed/NCBI
6	Shapiro MD and Fazio S: PCSK9 and atherosclerosis-lipids and beyond. J Atheroscler Thromb. 24:462–472. 2017. View Article : Google Scholar : PubMed/NCBI
7	Shahreyar M, Salem SA, Nayyar M, George LK, Garg N and Koshy SKG: Hyperlipidemia: Management with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. J Am Board Fam Med. 31:628–634. 2018. View Article : Google Scholar : PubMed/NCBI
8	Ochin CC and Garelnabi M: Berberine encapsulated PLGA-PEG nanoparticles modulate PCSK-9 in HepG2 Cells. Cardiovasc Hematol Disord Drug Targets. 18:61–70. 2018. View Article : Google Scholar : PubMed/NCBI
9	Tavori H, Rashid S and Fazio S: On the function and homeostasis of PCSK9: Reciprocal interaction with LDLR and additional lipid effects. Atherosclerosis. 238:264–270. 2015. View Article : Google Scholar :
10	Jeong HJ, Lee HS, Kim KS, Kim YK, Yoon D and Park SW: Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J Lipid Res. 49:399–409. 2008. View Article : Google Scholar
11	Krycer JR, Sharpe LJ, Luu W and Brown AJ: The Akt-SREBP nexus: Cell signaling meets lipid metabolism. Trends Endocrinol Metab. 21:268–276. 2010. View Article : Google Scholar : PubMed/NCBI
12	Cao X, Ding L, Xie ZZ, Yang Y, Whiteman M, Moore PK and Bian JS: A review of hydrogen sulfide synthesis, metabolism, and measurement: Is modulation of hydrogen sulfide a novel therapeutic for cancer? Antioxid Redox Signal. 2018. View Article : Google Scholar
13	Altaany Z, Moccia F, Munaron L, Mancardi D and Wang R: Hydrogen sulfide and endothelial dysfunction: Relationship with nitric oxide. Curr Med Chem. 21:3646–3661. 2014. View Article : Google Scholar : PubMed/NCBI
14	Wang Y, Wang X, Liang X, Wu J, Dong S, Li H, Jin M, Sun D, Zhang W and Zhong X: Inhibition of hydrogen sulfide on the proliferation of vascular smooth muscle cells involved in the modulation of calcium sensing receptor in high homocysteine. Exp Cell Res. 347:184–191. 2016. View Article : Google Scholar : PubMed/NCBI
15	Cheung SH and Lau JYW: Hydrogen sulfide mediates atheroprotection against oxidative stress via S-sulfhydration. PLoS One. 13:e01941762018. View Article : Google Scholar
16	Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, et al: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 34:154–156. 2003. View Article : Google Scholar : PubMed/NCBI
17	Singh A and Davidson M: Update on PCSK9 therapies for the treatment of dyslipidemia. Expert Rev Endocrinol Metab. 11:87–95. 2016. View Article : Google Scholar : PubMed/NCBI
18	Shapiro MD, Tavori H and Fazio S: PCSK9: From basic science discoveries to clinical trials. Circ Res. 122:1420–1438. 2018. View Article : Google Scholar : PubMed/NCBI
19	Elbitar S, Susan-Resiga D, Ghaleb Y, El Khoury P, Peloso G, Stitziel N, Rabès JP, Carreau V, Hamelin J, Ben-Djoudi-Ouadda A, et al: New sequencing technologies help revealing unexpected mutations in autosomal dominant hypercholesterolemia. Sci Rep. 8:19432018. View Article : Google Scholar : PubMed/NCBI
20	Reiss AB, Shah N, Muhieddine D, Zhen J, Yudkevich J, Kasselman LJ and DeLeon J: PCSK9 in cholesterol metabolism: From bench to bedside. Clin Sci (Lond). 132:1135–1153. 2018. View Article : Google Scholar
21	Spigoni V, Aldigeri R, Antonini M, Micheli MM, Fantuzzi F, Fratter A, Pellizzato M, Derlindati E, Zavaroni I, Bonadonna RC and Dei Cas A: Effects of a new nutraceutical formulation (berberine, red yeast rice and chitosan) on non-HDL cholesterol levels in individuals with dyslipidemia: Results from a randomized, double blind, placebo-controlled study. Int J Mol Sci. 18:E14982017. View Article : Google Scholar : PubMed/NCBI
22	Poirier S, Hamouda HA, Villeneuve L, Demers A and Mayer G: Trafficking dynamics of PCSK9-induced LDLR degradation: Focus on human PCSK9 mutations and C-terminal domain. PLoS One. 11:e01572302016. View Article : Google Scholar : PubMed/NCBI
23	Tavori H, Giunzioni I, Predazzi IM, Plubell D, Shivinsky A, Miles J, Devay RM, Liang H, Rashid S, Linton MF and Fazio S: Human PCSK9 promotes hepatic lipogenesis and atherosclerosis development via apoE- and LDLR-mediated mechanisms. Cardiovasc Res. 110:268–278. 2016. View Article : Google Scholar : PubMed/NCBI
24	Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, Prather HB, Anderson NN, Ho YK, Hammer RE and Horton JD: Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest. 116:2995–3005. 2006. View Article : Google Scholar : PubMed/NCBI
25	Qu K, Liu YM, He XL, Zhang H, Zhang K, Peng J, Tang YL, Yu XH, Zeng JF, Lei JJ, et al: H2 S inhibits apo(a) expression and secretion through PKCα/FXR and Akt/HNF4α pathways in HepG2 cells. Cell Biol Int. 40:906–916. 2016. View Article : Google Scholar : PubMed/NCBI
26	Park SW, Moon YA and Horton JD: Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem. 279:50630–50638. 2004. View Article : Google Scholar : PubMed/NCBI
27	Horton JD, Goldstein JL and Brown MS: SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 109:1125–1131. 2002. View Article : Google Scholar : PubMed/NCBI
28	Lebeau P, Al-Hashimi A, Sood S, Lhoták Š, Yu P, Gyulay G, Paré G, Chen SR, Trigatti B, Prat A, et al: Endoplasmic reticulum stress and Ca²⁺ depletion differentially modulate the sterol regulatory protein PCSK9 to control lipid metabolism. J Biol Chem. 292:1510–1523. 2017. View Article : Google Scholar
29	Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L and Prat A: Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 24:1454–1459. 2004. View Article : Google Scholar : PubMed/NCBI
30	Chae HS, You BH, Kim DY, Lee H, Ko HW, Ko HJ, Choi YH, Choi SS and Chin YW: Sauchinone controls hepatic cholesterol homeostasis by the negative regulation of PCSK9 transcriptional network. Sci Rep. 8:67372018. View Article : Google Scholar : PubMed/NCBI
31	Huang J, Chen S, Cai D, Bian D and Wang F: Long noncoding RNA lncARSR promotes hepatic cholesterol biosynthesis via modulating Akt/SREBP-2/HMGCR pathway. Life Sci. 203:48–53. 2018. View Article : Google Scholar : PubMed/NCBI
32	Zheng D, Chen Z, Chen J, Zhuang X, Feng J and Li J: Exogenous hydrogen sulfide exerts proliferation, anti-apoptosis, migration effects and accelerates cell cycle progression in multiple myeloma cells via activating the Akt pathway. Oncol Rep. 36:1909–1916. 2016. View Article : Google Scholar : PubMed/NCBI
33	Gong D, Cheng HP, Xie W, Zhang M, Liu D, Lan G, Huang C, Zhao ZW, Chen LY, Yao F, et al: Cystathionine γ-lyase(CSE)/hydrogen sulfide system is regulated by miR-216a and influences cholesterol efflux in macrophages via the PI3K/AKT/ABCA1 pathway. Biochem Biophys Res Commun. 470:107–116. 2016. View Article : Google Scholar : PubMed/NCBI
34	He NY, Li Q, Wu CY, Ren Z, Gao Y, Pan LH, Wang MM, Wen HY, Jiang ZS, Tang ZH and Liu LS: Lowering serum lipids via PCSK9-targeting drugs: Current advances and future perspectives. Acta Pharmacol Sin. 38:301–311. 2017. View Article : Google Scholar : PubMed/NCBI