1. Relevance

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide becoming the most frequent indication for liver transplantation due to progression of non-alcoholic steatohepatitis (NASH). It affects 25% of adults worldwide [1].

NAFLD is characterized by fat accumulation (> 5%) in hepatocytes called liver steatosis, without other causes of liver disease such as viral hepatitis, increased alcohol consumption or any chronic liver disease [2]. But it can progress to NASH or steatohepatitis, which is a liver steatosis with severe liver damage (canine degeneration of hepatocytes), inflammation of the liver and fibrosis. Further progression can lead to liver lesions, liver cirrhosis, terminal liver disease, portal hypertension (PG) and, in rare cases, hepatocellular carcinoma (HCC). NAFLD/NASH is also associated with other diseases. such as metabolic syndrome (MS), cardiovascular disease (CD), diabetes mellitus (DM) and obesity [3]. Being closely related to insulin resistance (IR) and central obesity, NAFLD is considered to be an increased risk of cardiovascular disease, especially atherosclerosis. In fact, NAFLD/NASH has the highest risk of death in NAFLD/NASH patients with cardiovascular disease than just liver disease. The development of NAFLD and its progression to NASH is not well understood. Various factors affecting the development of liver steatosis and its progression to NASH may be related to the availability of free fatty acid (FFA) due to IR and increased peripheral lipolysis, increased synthesis and reduced exports of triglycerides via very low density lipoproteins (VLDLP), inflammatory cytokines and adipokines, oxidative stress of the liver, mitochondrial and peroxidative dysfunction, and from intestinal microbiota [4]. Intrahepatic fibrosis is an established risk factor for cirrhosis, hepatocellular carcinoma and life-threatening liver failure.

At present, the main treatment for NAFLD/NASH is a change in lifestyle with reduced calorific intake, weight loss and exercise. No pharmacological treatment has been approved, there are still no standards for the treatment of FGM, but the use of insulin-stabilizing drugs, hypolipidemic drugs and antioxidants is practiced [9]. Pharmacotherapy, aimed at the underlying pathophysiology of this increasingly common disease, must be found and can stop its progression with lethal outcomes. Statins may be a strong candidate from this point of view, since they are lipid-reducing and general cholesterol-reducing agents that are 3-hydroxymethylglutaryl-coterment A (HMG CoA) reduction inhibitors, an enzyme that limits the rate of cholesterol synthesis, they are also pleiotropic. Their pleiotropic effects include anti-inflammatory, anti-proliferative, antioxidant, etc. as well as antithrombotic, anti-cancer and immunomodulating, which reduces inflammation and fibrosis in patients with NAFLD/NASH [10]. According to various studies, statins reduce hepatic steatosis by reducing oxidative stress and by increasing hepatic antioxidant paraoxonase1 (PON1) [11] and increasing mitochondrial and peroxisomal oxidation and induction of alpha receptor, Genome-activated peroxide proliferation (PPARα), fatty acid oxidation (FAO) [12]. They also reduce hepatic inflammation by reducing the expression of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and transformative growth factor beta 1 (TGF-β1) [13]. In addition, statins reduce fibrogenesis in NASH by improving endothelial dysfunction with the recovery of sinusoidal liver space and stabilization of stellated cells, as well as increasing nitrogen endothelial oxide content and synthase activity (eNOS) [14-16]. Statins are thought to protect against GTC as they reduce the expression in the liver of angiogenic factors such as the receptor of the vascular endothelial growth factor (VEGFR), the epidermal growth factor receptor (EGFR) and the platelet growth factor (PDGF) [13]. In addition, statins also reduce the level of [17] isoprenoids and eliminate cholesterol crystals, corona-like structures (CLS) [18] and inactivate stellated liver cells (HSC) [19] that prevent inflammation and fibrosis in NAVP / HAZG. In addition to the above, statins can play an important role in preventing, delaying and converting liver steatosis into NHA.

In addition, it has been reported that treatment with statins reduces the risk of atherosclerosis and mortality from CVS diseases associated with NAFLD. In other words, they are the only class of anti-hyperlipidemic agents that reduce CVS diseases at NAFLD [21]. Statins are generally considered to be anti-hyperlipidemic and their pleiotropic properties are not well understood. The study aims to review the medical literature to identify various pathogenic micro-organisms, the pathways of NAFLD progression to NASH, and the effectiveness of the statins in such cases. We hope this will help to justify a more diversified use of statins and subsequently raise awareness of their use in NAFLD and NASH. As NAFLD/NASH becomes a growing public health problem, To prevent and effectively treat statins, use can be a breakthrough because NASH has the highest risk of cardiovascular disease, But dyslipidemia also remains insufficiently studied for treatment.

In the last year, there have also been a number of scientific articles on the use of statins in the complex treatment of SARS-COV-2 and the outcome of pneumonia caused by this virus.

2. Pathogenesis COVID-19

SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2), which is present on type II pneumocytes in the lungs and on cell surfaces in the endothelial of the heart and vessels. The viral infusion is facilitated by the interaction of the receptor-binding domain in viral spike glycoprotein with ACE2 receptors [22,23]. Within cells, the virus is replicated, followed by exocytosis and release of mature viruses [22]. The endocytic activity involved in the penetration of the injectable virus activates the activity of the domains 17 disintegrin and metalloprotease, which removes ACE2 from the cell membrane. ACE2 is responsible for the transformation of angiotensin II into angiotensin 1-7, which has several benefits including vascular, anti-inflammatory and antifibrotic [9,24]. Consequently, the reduced availability of ACE2 on the cell surface results in the loss of ACE2-mediated protection from the harmful effects of tissue renin angiotensin-aldosterone.

SARS-CoV-2 can also cause multi-system inflammatory disease, a cascade due to a cytokine storm by activating IL-6, IL-8, TNF-a. A cascade of an inflammatory process is launched, leading to an increase in the production of pro-inflammatory agents such as interleukin-1 (IL-1), IL-2, IL-3, IL-4, IL-6, which cause increased vessel permeability, alveolar damage to epithelium, etc. leading to acute respiratory distress syndrome [16,22].

COVID-19 infections also lead to coagulopathy and thromboembolism complications such as systemic venous thrombosis and pulmonary embolism.

3. Possible Static Mechanisms at COVID-19

Statins have several different effects related to COVID-19.

Anti-inflammatory effect. As anti-inflammatory agents, statins inhibit isoprenoid synthesis, which plays an important role in inflammation. Statins inhibit leukocyte adhesion, activation of T cell molecule [25]. Statins reduce the expression of proxy cytokines such as IL-6, IL-8 and chemotoxicity protein-1 monocytes, thereby altering the inflammatory path of damage to host cells [11,12,26].

Impact on virus cell penetration Several different theories have been proposed to describe the potential effects of statins on the penetration of SARS-CoV-2 into human cells. Both beneficial and adverse effects were proposed.

The role of cholesterol in cell membranes. The SARS-CoV-2 binding spikes to ACE2 receptors present on cell surfaces are facilitated by the presence of lipid rafts on cell membranes. Cholesterol depletion of cell membranes with agents such as cyclodextrin has been shown to inhibit the process and prevent the virus from entering cells. Conversely, the enrichment of cell membranes with cholesterol may contribute to the spread of the virus [28,29].

The effect of statins on cholesterol in cell membranes is already known. Some researchers believe that statins, by reducing endogenous cholesterol synthesis, deplete cell membranes and reduce cholesterol [30]. In contrast, other researchers have suggested that decreasing circulating cholesterol increases regulation of low-density lipoprotein receptors on the cell surface, thereby increasing cholesterol uptake from blood [14,17]. Statins also inhibit acyl CoA: cholesterol acyltransferase (ACAT) present in the endoplasmic reticulum, which is also responsible for the removal of cholesterol from cell membranes. A recent study has shown that SARS-CoV-2 causes one of the interferon-stimulated genes of cholesterol-25-hydroxylase (CH25H) in vitro and in patients with COVID-19. CH25H turns cholesterol into 25-hydrocholesterol (25HC), which activates ACAT, thus preventing the fusion of SARS-CoV-2 to cell membranes and the virus from entering cells. The effect of 25HC on preventing uptake in lung epithelial cells has been specifically demonstrated [27]. However, studies using human culture respiratory epithelium cells have shown that statins such as fluvanstatin successfully inhibit the penetration of SARS-CoV-2 into cells [20].

4. Influence on Expression Inhibitor ACE

Statins, like APP inhibitors and angiotensin receptor blockers, are known to increase ACE2 regulation by expressing on human cells [5,6]. It has been suggested that this effect may increase susceptibility to SARS-CoV-2 infection. Conversely, increased expression of ACE2 is expected to be a beneficial effect rather than a harmful one [10,23]. ACE2-mediated transformation of angiotensin II to angiotensin I [12,19] takes place as shown, thus minimizing lung damage in patients infected with coronavirus [31].

Other mechanisms. Recent studies have suggested that statins inhibit the main protease of SARS-CoV-2, i.e. the key enzyme of the coronavirus [26]. Disruption of this protease activity can affect viral infection by inhibiting viral glycoprotein. However, it is not clear whether this effect is also observed at statin concentrations in doses used in clinical conditions.

Cardiovascular advantages. Epidemiological studies have shown that patients with pre-existing cardiovascular disease are at greater risk of infection as well as of developing severe COVID-19 [27,28]. At the same time, COVID-19 itself can lead to a number of cardiovascular complications. Statins have a well-known effectiveness in reducing the risk of cardiovascular events in a wide range of patients [19,25]. Therefore, in addition to any potential direct effects of statins on COVID-19, statins as such help reduce the risk of cardiovascular complications in these patients and improve the clinical course of the disease and outcome.

Clinical results of statins at COVID-19. Several observational studies have evaluated the potentially positive role of statins in COVID-19 [31]. Zhang et al. conducted a large retrospective cohort study of 13.981 patients with COVID-19 in Hubei Province in China, of which 1219 received statins [21]. They observed a significantly lower 28-day mortality in the group of statins (5.5 per cent mortality) than in the group not taking statins (6.8 per cent mortality, P = 0.046). Cox’s study found that the risk of 28 days of mortality from all causes was 5.2% in the group of statins and 9.4% in the group that did not accept statins, with an adjusted risk ratio of 0.58. Patients taking statins also had lower levels of C-reactive protein and IL-6 [23,28].

Daniels et al. recently published a retrospective single center study that examined all patients hospitalized at their center between February 10, 2020 and June 17, 2020. [30]. A total of 170 patients were diagnosed with SARS-CoV-2, of whom 53% developed a severe disease. It was noted that the use of statins prior to hospitalization was associated with a significantly lower risk of developing severe COVID disease (the adjusted odds ratio of 0.29, 95 confidence intervals from 0.11 to 0.71, p <0.01). Statins have also been associated with faster recovery times in those who do not have a severe disease after control of comorbidity. The beneficial effect of using statins to reduce the risk of developing a severe disease was also observed in patients with negative COVID status in the hospital (n = 5281), but this association was much weaker than in patients with coronavirus [28,36].

It can be concluded that those with a viral infection who received statins were much easier to carry pneumonia, despite the age and discharge from hospital was earlier by 3-4 days. Almost all patients were not affected by the cytokine storm.

5. Conclusions

This review, based on a sufficient number of studies, proves the effectiveness of statins through their pleiotropic and hypolipidemic actions against NAFLD/NASH -associated inflammation and fibrosis. Statins achieve this by acting on different target points, inhibiting RhoA and Ras, increasing PPARα expression, lowering PON1 levels, preventing liver sinusoidal endothelial cell dedifferentiation and HSC activation, or allowing KC corona-like structures. Moreover, they also improve the adverse outcomes associated with NASH, such as MS, cardiovascular disease morbidity and mortality and hepatocellular carcinoma (HCC) prevention, are considered safe. These results of the study brought the drug closer to addressing the future use of statins as routine care in clinical practice at NAFLD/NASH. If confirmed by larger and longer-term clinical trials, statins may prove to be promising treatments for NASH, which remains an unresolved problem.