Ganoderic acid A ameliorates non‑alcoholic streatohepatitis (NASH) induced by high‑fat high‑cholesterol diet in mice

Zhu,Jing; Ding,Jiexia; Li,Siying; Jin,Jie

doi:10.3892/etm.2022.11237

Ganoderic acid A ameliorates non‑alcoholic streatohepatitis (NASH) induced by high‑fat high‑cholesterol diet in mice

Authors:
- Jing Zhu
- Jiexia Ding
- Siying Li
- Jie Jin
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Affiliations: Department of Infectious Diseases, The Fourth Clinical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
Published online on: February 24, 2022 https://doi.org/10.3892/etm.2022.11237
Article Number: 308
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Non‑alcoholic steatohepatitis (NASH) is becoming a huge global health problem. Previous studies have revealed that ganoderic acids have hepatoprotective and hypocholesterolemic effects. In the present study, to evaluate the anti‑NASH activity of ganoderic acid A (GAA), male 6‑week‑old C57BL/6J mice were divided into the following four groups, which were administered different diets: Normal diet (ND group), high‑fat high‑cholesterol diet (HFHC group), HFHC diet supplemented with 25 mg/kg/day (GAAL group) or 50 mg/kg/day of GAA (GAAH group). After 12 weeks of GAA treatment, histopathological results revealed that compared with that of the HFHC group, GAA significantly inhibited fat accumulation, steatosis, inflammation and fibrosis in the liver. GAA effectively reduced serum aspartate transaminase and alanine transaminase levels compared with the HFHC model. Furthermore, the endoplasmic reticulum (ER) stress‑responsive proteins, including glucose‑regulated protein 78, phosphorylated (p)‑eukaryotic initiation factor‑2α and p‑JNK, were significantly suppressed by GAA, while ERp57, p‑MAPK and p‑AKT were significantly increased after GAA treatment. Taken together, it was concluded that GAA could resist HFHC diet‑induced NASH. In terms of its underlying mechanism, GAA could improve liver inflammation and fibrosis by inhibiting hepatic oxidative stress and the ER stress response induced by HFHC.

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1	Kitade H, Chen G, Ni Y and Ota T: Nonalcoholic fatty liver disease and insulin resistance: New insights and potential new treatments. Nutrients. 9(387)2017.PubMed/NCBI View Article : Google Scholar
2	Milic S, Lulic D and Stimac D: Non-alcoholic fatty liver disease and obesity: Biochemical, metabolic and clinical presentations. World J Gastroenterol. 20:9330–9337. 2014.PubMed/NCBI View Article : Google Scholar
3	Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA and Ikramuddin S: Nonalcoholic steatohepatitis: A review. JAMA. 323:1175–1183. 2020.PubMed/NCBI View Article : Google Scholar
4	Anstee QM, Reeves HL, Kotsiliti E, Govaere O and Heikenwalder M: From NASH to HCC: Current concepts and future challenges. Nat Rev Gastroenterol Hepatol. 16:411–428. 2019.PubMed/NCBI View Article : Google Scholar
5	Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J and Bugianesi E: Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 15:11–20. 2018.PubMed/NCBI View Article : Google Scholar
6	Bonora E and Targher G: Increased risk of cardiovascular disease and chronic kidney disease in NAFLD. Nat Rev Gastroenterol Hepatol. 9:372–381. 2012.PubMed/NCBI View Article : Google Scholar
7	Ferguson D and Finck BN: Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus. Nat Rev Endocrinol. 17:484–495. 2021.PubMed/NCBI View Article : Google Scholar
8	Buzzetti E, Pinzani M and Tsochatzis EA: The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 65:1038–1048. 2016.PubMed/NCBI View Article : Google Scholar
9	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.PubMed/NCBI View Article : Google Scholar
10	Han J and Kaufman RJ: The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res. 57:1329–1338. 2016.PubMed/NCBI View Article : Google Scholar
11	Yan J and Horng T: Lipid metabolism in regulation of macrophage functions. Trends Cell Biol. 30:979–989. 2020.PubMed/NCBI View Article : Google Scholar
12	Wachtel-Galor S, Yuen J, Buswell JA and Benzie IFF: Ganoderma lucidum (Lingzhi or Reishi): A Medicinal Mushroom. In: Herbal Medicine: Biomolecular and Clinical Aspects. Benzie IFF and Wachtel-Galor S (eds). 2nd edition. CRC Press/Taylor & Francis, Boca Raton, FL, 2011.
13	Paterson RR: Ganoderma-a therapeutic fungal biofactory. Phytochemistry. 67:1985–2001. 2006.PubMed/NCBI View Article : Google Scholar
14	Sliva D: Cellular and physiological effects of Ganoderma lucidum (Reishi). Mini Rev Med Chem. 4:873–879. 2004.PubMed/NCBI View Article : Google Scholar
15	Tong CC, Choong YK, Mohamed S, Mustapha NM and Umar NA: Nutrition & Food Science. Efficacy of Ganoderma lucidum on plasma lipids and lipoproteins in rats fed with high cholesterol diet. Nutrition Food Sci. 38:229–238. 2008.
16	Wasser SP: Reishi or ling zhi (Ganoderma lucidum). Encyclopedia Dietary Suppl. 1:603–622. 2005.
17	Kabir Y, Kimura S and Tamura T: Dietary effect of Ganoderma lucidum mushroom on blood pressure and lipid levels in spontaneously hypertensive rats (SHR). J Nutr Sci Vitaminol. 34:433–438. 1988.PubMed/NCBI View Article : Google Scholar
18	Li C, Li Y and Sun HH: New ganoderic acids, bioactive triterpenoid metabolites from the mushroom Ganoderma lucidum. Nat Prod Res. 20:985–991. 2006.PubMed/NCBI View Article : Google Scholar
19	Xu JW, Zhao W and Zhong JJ: Biotechnological production and application of ganoderic acids. Appl Microbiol Biotechnol. 87:457–466. 2010.PubMed/NCBI View Article : Google Scholar
20	Zhu J, Jin J, Ding J, Li S, Cen P, Wang K, Wang H and Xia J: Ganoderic Acid A improves high fat diet-induced obesity, lipid accumulation and insulin sensitivity through regulating SREBP pathway. Chem Biol Interact. 290:77–87. 2018.PubMed/NCBI View Article : Google Scholar
21	Lang S, Demir M, Martin A, Jiang L, Zhang X, Duan Y, Gao B, Wisplinghoff H, Kasper P, Roderburg C, et al: Intestinal virome signature associated with severity of nonalcoholic fatty liver disease. Gastroenterology. 159:1839–1852. 2020.PubMed/NCBI View Article : Google Scholar
22	Sun R, Liang H, Guo H, Wang Z and Deng Q: PMCA4 gene expression is regulated by the androgen receptor in the mouse testis during spermatogenesis. Mol Med Rep. 23(152)2021.PubMed/NCBI View Article : Google Scholar
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
24	Ucar F, Sezer S, Erdogan S, Akyol S, Armutcu F and Akyol OJ: The relationship between oxidative stress and nonalcoholic fatty liver disease: Its effects on the development of nonalcoholic steatohepatitis. Redox Rep. 18:127–133. 2013.PubMed/NCBI View Article : Google Scholar
25	Pan K, Jiang Q, Liu G, Miao X and Zhong D: Optimization extraction of Ganoderma lucidum polysaccharides and its immunity and antioxidant activities. Int J Biol Macromol. 55:301–306. 2013.PubMed/NCBI View Article : Google Scholar
26	Liang C, Tian D, Liu Y, Li H, Zhu J, Li M, Xin M and Xia J: Review of the molecular mechanisms of Ganoderma lucidum triterpenoids: Ganoderic acids A, C2, D, F, DM, X and Y. Eur J Med Chem. 174:130–141. 2019.PubMed/NCBI View Article : Google Scholar
27	Boh B, Berovic M, Zhang J and Zhi-Bin L: Ganoderma lucidum and its pharmaceutically active compounds. Biotechnol Annu Rev. 13:265–301. 2007.PubMed/NCBI View Article : Google Scholar
28	Liu F, Shi K, Dong J, Jin Z, Wu Y, Cai Y, Lin T, Cai Q, Liu L and Zhang Y: Ganoderic acid A attenuates high-fat-diet-induced liver injury in rats by regulating the lipid oxidation and liver inflammation. Arch Pharm Res. 43:744–754. 2020.PubMed/NCBI View Article : Google Scholar
29	Wu GS, Lu JJ, Guo JJ, Li YB, Tan W, Dang YY, Zhong ZF, Xu ZT, Chen XP and Wang YT: Ganoderic acid DM, a natural triterpenoid, induces DNA damage, G1 cell cycle arrest and apoptosis in human breast cancer cells. Fitoterapia. 83:408–414. 2012.PubMed/NCBI View Article : Google Scholar
30	Lixin X, Lijun Y and Songping H: Ganoderic acid A against cyclophosphamide-induced hepatic toxicity in mice. J Biochem Mol Toxicol. 33(e22271)2019.PubMed/NCBI View Article : Google Scholar
31	Bessone F, Razori MV and Roma MG: Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci. 76:99–128. 2019.PubMed/NCBI View Article : Google Scholar
32	Bala S, Ganz M, Babuta M, Zhuang Y, Csak T, Calenda CD and Szabo G: Steatosis, inflammasome upregulation, and fibrosis are attenuated in miR-155 deficient mice in a high fat-cholesterol-sugar diet-induced model of NASH. Lab Invest. 101:1540–1549. 2021.PubMed/NCBI View Article : Google Scholar
33	Ma JQ, Zhang YJ and Tian ZK: Anti-oxidant, anti-inflammatory and anti-fibrosis effects of ganoderic acid A on carbon tetrachloride induced nephrotoxicity by regulating the Trx/TrxR and JAK/ROCK pathway. Chem Biol Interact. 344(109529)2021.PubMed/NCBI View Article : Google Scholar
34	Ganz M and Szabo G: Immune and inflammatory pathways in NASH. Hepatol Int. 7 (Suppl 2):S771–S781. 2013.PubMed/NCBI View Article : Google Scholar
35	Heebøll S, Thomsen KL, Clouston A, Sundelin EI, Radko Y, Christensen LP, Ramezani-Moghadam M, Kreutzfeldt M, Pedersen SB, Jessen N, et al: Effect of resveratrol on experimental non-alcoholic steatohepatitis. Pharmacol Res. 95-96:34–41. 2015.PubMed/NCBI View Article : Google Scholar
36	Ji G, Wang Y, Deng Y, Li X and Jiang Z: Resveratrol ameliorates hepatic steatosis and inflammation in methionine/choline-deficient diet-induced steatohepatitis through regulating autophagy. Lipids Health Dis. 14(134)2015.PubMed/NCBI View Article : Google Scholar
37	Kessoku T, Imajo K, Honda Y, Kato T, Ogawa Y, Tomeno W, Kato S, Mawatari H, Fujita K, Yoneda M, et al: Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Sci Rep. 6(22251)2016.PubMed/NCBI View Article : Google Scholar
38	Trautwein C, Friedman SL, Schuppan D and Pinzani M: Hepatic fibrosis: Concept to treatment. J Hepatol. 62 (Suppl 1):S15–S24. 2015.PubMed/NCBI View Article : Google Scholar
39	Arroyave-Ospina JC, Wu Z, Geng Y and Moshage H: Role of oxidative stress in the pathogenesis of non-alcoholic fatty liver disease: Implications for prevention and therapy. Antioxidants (Basel). 10(174)2021.PubMed/NCBI View Article : Google Scholar
40	Chen Z, Tian R, She Z, Cai J and Li H: Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease. Free Radic Biol Med. 152:116–141. 2020.PubMed/NCBI View Article : Google Scholar
41	Darling NJ and Cook SJ: The role of MAPK signalling pathways in the response to endoplasmic reticulum stress. Biochim Biophys Acta. 1843:2150–2163. 2014.PubMed/NCBI View Article : Google Scholar
42	Parakh S, Jagaraj CJ, Vidal M, Ragagnin AMG, Perri ER, Konopka A, Toth RP, Galper J, Blair IP, Thomas CJ, et al: ERp57 is protective against mutant SOD1-induced cellular pathology in amyotrophic lateral sclerosis. Hum Mol Genet. 27:1311–1331. 2018.PubMed/NCBI View Article : Google Scholar
43	Koruk M, Taysi S, Savas MC, Yilmaz O, Akcay F and Karakok M: Oxidative stress and enzymatic antioxidant status in patients with nonalcoholic steatohepatitis. Ann Clin Lab Sci. 34:57–62. 2004.PubMed/NCBI
44	Sutti S, Jindal A, Locatelli I, Vacchiano M, Gigliotti L, Bozzola C and Albano E: Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology. 59:886–897. 2014.PubMed/NCBI View Article : Google Scholar
45	Gabbia D, Cannella L and De Martin S: The Role of Oxidative Stress in NAFLD-NASH-HCC Transition-Focus on NADPH Oxidases. Biomedicines. 9(687)2021.PubMed/NCBI View Article : Google Scholar