1. Context
Non-alcoholic fatty liver disease (NAFLD) is among the most common causes of liver disorders worldwide (1-5), which may progress to nonalcoholic steatohepatitis (NASH) and hepatic cirrhosis (6-11). NAFLD usually develops due to the accumulation of fatty acids in hepatocytes, which can progress to steatohepatitis through rise in oxidative stress in the body (6, 12, 13). Due to the rising prevalence of obesity and sedentary life, NAFLD has become the most common cause of chronic liver disease (14-16).
Nigella sativa (NS), also known as black seed, is from Ranunculaceae family that is cultivated in Asia (17-20). The main components of NS are thymoquinone (TQ), unsaturated fatty acids, flavonoids, nigellone, p-cymene and carvone (19, 21-27).
It has been shown that nutrition and dietary supplements play a pivotal role in the treatment of NAFLD (28-40). Recently, some studies have evaluated the effects of medicinal herbs such as NS on some risk factors for NAFLD such as insulin resistance, hyperlipidemia, oxidative stress and inflammation in experimental models (41-44). In this study, we sought to review the results of these studies and find the future direction in this field of science.
2. Evidence Acquisition
We searched the literature published until 2017 using the following key words: “Nigella sativa”, “thymoquinone”, “black seeds”, “NAFLD”, NASH, and “diabetes”. Papers used in this study were collected by searching the PubMed, Google Scholar, Science Direct and Scopus databases and journals. To avoid the use of duplicate studies, titles and abstracts were screened. Then, compatibility of the selected articles was assessed according to our inclusion criteria. All the articles published between 2000 and 2017 meeting the inclusion criteria were included in the study. Review articles, case reports, conference abstracts and symposium publications were excluded.
3. Results
3.1. In Vitro and In Vivo Studies
In vitro and in vivo studies have shown some mechanisms for hepato-protective effects of TQ as the main effective component of NS. Bai et al. demonstrated the antifibrotic effects of TQ in their in vitro study. They found that these anti-fibrotic effects are attributed to the inhibition of apoptosis through attenuation in the expression of CD14, Toll-like receptor 4 (TLR4), α-SMA, collagen-I, X-linked inhibitor of apoptosis protein (XIAP), and expression of cellular FLIP (c-FLIPL) and other genes related to the regulation of apoptosis. Furthermore, these properties of TQ have been shown in in vivo studies (45). It has been proposed that TQ improves survival against LPS challenge in D-galactosamine (D-GlaN)-sensitized mice through the inhibition of TLR4 expression and PI3K phosphorylation. Therefore, it seems that TQ may be a potential candidate for hepatic fibrosis treatment (45).
Yang et al. ascribed that TQ has hepato-protective effects via AMP- activated protein kinase (AMPK) signaling in hepatic stellate cells (HSCs). They reported that TQ inhibits fibrogenic agents such as collagen-I and TGF-β, while inducing peroxisome proliferator activated receptor-γ (PPAR-γ) expression. Moreover, TQ (20 or 40 mg/kg) attenuated the rise in hepatic enzymes and triglycerides in an experimental model of alcoholic fatty liver disease (46). Moreover, there are some reports that supplementation with NS oil in experimental models of diabetes ameliorated serum sugar, oxidative stress, and hyperlipidemia after eight weeks and that essential oils were more effective than fixed oils (47, 48). Moreover, Awad et al. showed that TQ improves hepatic steatosis, oxidative stress, inflammatory and apoptotic status (49). Oguz et al. demonstrated that two weeks of supplementation with TQ (50 mg/kg) improved antioxidant enzyme activity in hepatic tissues (50). Furthermore, Kong et al. evaluated the effects of two dosages of TQ, low-dose (25 mg/kg) and high-dose (50 mg/kg); they observed that TQ reduced hepatic hydroxyproline (HP) and malondialdehyde (MDA) levels and increased antioxidant enzyme activity. Thus, TQ reduced oxidative stress injury and fibrosis in the liver (51).
3.2. Human Studies
Although there are some studies that have shown that NS consumption ameliorates some NAFLD risk factors such as fasting blood glucose and lipid profile (52), we could find only one study that evaluated the effects of NS on human subjects with NAFLD (53). This study evaluated the effects of 12 weeks of supplementation with 2 g/day of NS on body weight and liver enzymes. Although the study suffered from several limitations, it showed promising effects. Further well-designed studies are required in this regard to draw any conclusions.
3.3. Possible Mechanism of Action
It seems that NS improves lipid profile and glycemic indices through its anti-oxidative and insulin sensitizer properties. The main antioxidant components of NS are TQ and dithymoquinone (54). TQ can scavenge free radicals in different body tissues such as the liver (55). Moreover, NS contains other antioxidant agents such as tocopherols, phytosterols, and polyunsaturated fatty acids, which can protect cholesterol molecules from oxidation and inhibit the process of atherosclerosis (1). Anti-oxidative action of NS induces pancreatic beta cell regeneration and rise in their integrity, which result in more insulin secretion and less insulin resistance (56, 57).
Moreover, NS reduces glucose absorption by the inhibition of sodium–glucose co-transporter (58). All of these lead to reduction in insulin resistance and its related metabolic disturbances. Furthermore, it has been shown that NS can decline gluconeogenesis through reduction in gluconeogenic enzymes gene expression by TQ (59). Moreover, it has been shown that TQ up-regulates LDL-C receptors on hepatocytes to reduce the uptake of LDL-C; it also reduces the production of cholesterol by the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CO-A) reductase (60).
Another proposed mechanism for the beneficial effects of NS on NAFLD risk factors is through its effects on weight management. One-month supplementation of NS extract caused a significant reduction in food consumption and body weight in experimental models and human studies (61).
4. Conclusions
Results from available studies indicate that NS can ameliorate the main metabolic disturbances related to NAFLD including hyperglycemia, hyperlipidemia and overweight. These effects are mainly attributed to anti-oxidative and anti-inflammatory properties of TQ. Clinical trials on human subjects are highly essential to confirm the results found in in vivo and in vitro studies.
