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

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 antiinflammatory 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.

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

“…Statins are potent cholesterol-lowering agents and evidenced-based drugs to reduce CV outcomes. Their cholesterol-lowering efficacy is expected to be beneficial for NAFLD, which is characterized by aggregation of free cholesterol into hepatocytes[ 22 , 23 ]. Besides, statins have been suggested to exert variable lipid-independent pleiotropic benefits, including antioxidant, anti-thrombotic, anti-fibrotic and anti-inflammatory actions as well as endothelial function improvement.…”

Targeting Liver Sinusoidal Endothelial Cells: An Attractive Therapeutic Strategy to Control Inflammation in Nonalcoholic Fatty Liver Disease

“…Therefore, the dysfunction of LSECs promotes activation of KCs, which in turn contributes to the morphological changes and activation of LSECs, and this interaction leads to exacerbation of liver inflammatory response in the early stage of NAFLD. Certainly, ameliorating endothelial dysfunction of LSECs can improve liver inflammation in animal models by manipulating the NO signal pathway using sildenafil or simvastatin (Tateya et al, 2011;Wang et al, 2013;Ahsan et al, 2020).…”

“…Praliciguat, a soluble guanylate cyclase stimulator, effectively reduced inflammation, fibrosis, and steatosis by enhancing NO signaling in preclinical NASH models (Hall et al, 2019). Besides, improvement of the NO/cGMP signaling pathway by using phosphodiesterase-5 inhibitor sildenafil or simvastatin prevented liver inflammation in NAFLD rodents fed HFD (Tateya et al, 2011;Wang et al, 2013;Ahsan et al, 2020).…”

Endothelial dysfunction in pathological processes of chronic liver disease during aging

“…Furthermore, iNOS inhibition alleviated liver endothelial dysfunction, reduced nitrooxidative stress and delayed the development of liver injury 65 . Another latest study reported that statins may restore a healthy LSEC and HSC by inhibiting the activation of HSC through modulating the expression of iNOS and eNOS 66 . But in fact, there are few studies about the changes of iNOS in aging LSECs and the subsequent effects in chronic liver diseases during aging.…”