Pleiotropic Effects of Statins in the Light of Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

Farah Ahsan, Federico Oliveri, Harshit K Goud, Zainab Mehkari, Lubna Mohammed, Moiz Javed, Aldanah Althwanay, Ian H Rutkofsky, Farah Ahsan, Federico Oliveri, Harshit K Goud, Zainab Mehkari, Lubna Mohammed, Moiz Javed, Aldanah Althwanay, Ian H Rutkofsky

Abstract

Statins, the lipid-lowering drugs, and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), a lipid-related pathology, share a complex relationship, one known to be hepatotoxic and other being hepatic injury. NASH is an unresolved mystery in terms of treatment. Could statins prove to be a promising solution due to their pleiotropic properties in addition to the cholesterol-lowering effect? This study aims to find statin effectiveness in NAFLD/NASH treatment and prevention of associated adverse outcomes. An extensive data search was done to identify the studies assessing statin effect on NAFLD/NASH and then analyzed to establish the relationship. Several studies demonstrated a reduction in NAFLD/NASH-associated inflammation and fibrosis with statin treatment. These anti-inflammatory and anti-fibrotic effects were through their pleiotropic properties, which were in addition to their cholesterol-lowering effect. In various animal studies, statins were found to improve hepatic lipotoxicity, oxidative stress, inflammatory responses, and fibrosis associated with NASH through multiple pathways. Statins exert these protective effects by recovering the gene expression level of peroxisomal proliferator-activated receptor alpha (PPARα) and therefore restore the mitochondrial and peroxisomal fatty acid oxidation (FAO). Statin treatment also increased the levels of paraoxonase 1 (PON1), an antioxidant and antiatherogenic enzyme that is reduced in NAFLD as well as encounter the hepatic lipotoxicity by resolving cholesterol crystals and Kupffer cells (KCs) with crown-like structures (CLSs). They exhibited antitumor properties by inhibiting proinflammatory cytokines and vascular proliferative factors. Moreover, they restored a healthy liver sinusoidal endothelial cell (LSEC) and hepatic stellate cells (HSC) along with inhibiting the activation of HSC via modulating inducible nitric oxide synthase (iNOS) and expressions of endothelial nitric oxide synthase (eNOS). Besides, they were protective against cardiovascular disease (CVD)-related morbidity and mortality, hepatocellular carcinoma (HCC), and metabolic syndrome (MS) associated with NAFLD/NASH. NASH and its precursor, NAFLD, could be treated and prevented with statins owing to their pleiotropic properties. This study helps to prove this by looking back at different literature and has successfully enlightened the point. Once proved through large clinical trials on humans, it could revolutionize the NASH therapy.

Keywords: cytokines; fatty acid oxidation; nafld; nash; nash and statins; statins; steatosis.

Conflict of interest statement

The authors have declared that no competing interests exist.

Copyright © 2020, Ahsan et al.

Figures

Figure 1. Non-alcoholic fatty liver disease pathogenesis…
Figure 1. Non-alcoholic fatty liver disease pathogenesis and statins
NAFLD - Nonalcoholic fatty liver disease NASH - Non-alcoholic steatohepatitis HCC - Hepatocellular carcinoma
Figure 2. Pleiotropic effects of statins
Figure 2. Pleiotropic effects of statins
PON1 - Paraoxonase 1, PPARα - Peroxisomal proliferator-activated receptor alpha, LSEC - liver sinusoidal endothelial cell, HSC - Hepatic stellate cells, KCs - Kupffer cells, CLSs - crown-like structures

References

    1. Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: implications for liver transplantation. Younossi ZM, Marchesini G, Pinto-Cortez H, et al. Transplantation. 2019;103:22–27.
    1. Non-alcoholic fatty liver disease: what has changed in the treatment since the beginning? Baran B, Akyüz F. World J Gastroenterol. 2014;20:14219–14229.
    1. Clinical approaches to non-alcoholic fatty liver disease. Schwenger KJ, Allard JP. World J Gastroenterol. 2014;20:1712–1723.
    1. Pathogenesis of non-alcoholic fatty liver disease. Dowman JK, Tomlinson JW, Newsome PN. QJM. 2010;103:71–83.
    1. Nonalcoholic fatty liver disease: a review and update. Lewis JR, Mohanty SR. Dig Dis Sci. 2010;55:560–578.
    1. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Ekstedt M, Hagstrom H, Nasr P, et al. Hepatology. 2015;61:1547–1554.
    1. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Younossi ZM, Stepanova M, Rafiq N, et al. Hepatology. 2011;53:1874–1882.
    1. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Kim D, Kim WR, Kim HJ, et al. Hepatology. 2013;57:1357–1365.
    1. A critical approach of guideline therapeutic recommendations for NAFLD. Djordjevic DB, Zdravkovic M, Nagorni Nagorni, et al. Curr Vasc Pharmacol. 2018;16:228–238.
    1. Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells. Lee WC, Yi CH, Ting FL, et al. BMC Gastroenterol. 2015;15:22.
    1. Paraoxonase-1 activity, malondialdehyde and glutathione peroxidase in non-alcoholic fatty liver disease and the effect of atorvastatin. Samy W, Hassanian MA. Arab J Gastroenterol. 2011;12:80–85.
    1. Statins increase mitochondrial and peroxisomal fatty acid oxidation in the liver and prevent non-alcoholic steatohepatitis in mice. Park HS, Jang JE, Ko MS, et al. Diabetes Metab J. 2016;40:376–385.
    1. Rosuvastatin as a potential preventive drug for the development of hepatocellular carcinoma associated with non-alcoholic fatty liver disease in mice. Yokohama K, Fukunishi S, Li M, et al. Int J Mol Med. 2016;38:1499–1506.
    1. Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats. Abraldes JG, Vilarrupla AR, Graupera M, et al. J Hepatol. 2007;46:1040–1046.
    1. The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins. Marrone G, Lucia R, Eugenio R, et al. J Hepatol. 2013;58:98–103.
    1. A nitric oxide-donating statin decreases portal pressure with a better toxicity profile than conventional statins in cirrhotic rats. Rodríguez S, Raurell I, Arauz MT, et al. Sci Rep. 2017;7:40461.
    1. Statins improve NASH via inhibition of RhoA and Ras. Schierwagen R, Maybüchen L, Hittatiya K, et al. Am J Physiol Gastrointest Liver Physiol. 2016;1:724–733.
    1. Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH. Ioannou GN, Rooyen DMV, Savard C, et al. J Lipid. 2015;56:277–285.
    1. Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis. Wang W, Zhao C, Zhou J, et al. PLoS One. 2013;8:76538.
    1. Judicious use of lipid lowering agents in the management of NAFLD. Iqbal U, Perumpail BJ, John N, et al. Diseases. 2018;6:87.
    1. Antioxidant therapy and drugs interfering with lipid metabolism: could they be effective in NAFLD patients? Musso G, Anty R, Petta S. Curr Pharm Des. 2013;19:5297–5313.
    1. Paraoxonase-1 serum concentration and PON1 gene polymorphisms: relationship with non-alcoholic fatty liver disease. Milaciu MV, Vesa SC, Bocsan IC, et al. J Clin Med. 2019;8:2200.
    1. Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH. Ioannou GN, Subramanian S, Chait A, et al. J Lipid Res. 2017;58:1067–1079.
    1. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Musso G, Cassader M, Gambino R. Nat Rev Drug Discov. 2016;15:249–274.
    1. Pleiotropic effects of statins - basic research and clinical perspectives. Zhou Q, Liao JK. Circ J. 2010;74:818–826.
    1. Pleiotropic effects of statins. Kavalipati N, Shah J, Ramakrishan A, et al. Indian J Endocrinol Metab. 2015;19:554–562.
    1. Restoration of liver sinusoidal cell phenotypes by statins improves portal hypertension and histology in rats with NASH. Bravo M, Raurell I, Hide D, et al. Sci Rep. 2019;9:20183.
    1. Statins: an under-appreciated asset for the prevention and the treatment of NAFLD or NASH and the related cardiovascular risk. Athyros VG, Boutari C, Stavropoulos K, et al. Curr Vasc Pharmacol. 2018;16:246–253.
    1. The role of statins in the management of nonalcoholic fatty liver disease. Doumas M, Imprialos K, Dimakopoulou A, et al. Curr Pharm Des. 2018;24:4587–4592.
    1. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome. Kargiotis K, Athyros VG, Giouleme O, et al. World J Gastroenterol. 2015;21:7860–7868.
    1. Liver safety of statins in prediabetes or T2DM and nonalcoholic steatohepatitis: post hoc analysis of a randomized trial. Bril F, Sanchez PP, Lomonaco R, et al. J Clin Endocrinol Metab. 2017;102:2950–2296.
    1. Statins for non-alcoholic fatty liver disease and nonalcoholic steatohepatitis. Eslami L, Merat S, Malekzadeh R, et al. Cochrane Database Syst Rev. 2013;12:8623.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する