2.1.3. Liver Disease

Nonalcoholic fatty liver disease (NAFLD) occurs when there is generation of fat in the liver in the absence of alcohol. NAFLD is characterized by lobular hepatitis, hepatic steatosis, and liver cell injury [62]. One of the mechanisms involved in the pathogenesis of NAFLD is the inflammation in hepatocytes [63]. Nuclear receptor such as Liver X receptor α (LXR-α) and peroxisome proliferator-activated receptor α (PPAR-α) are responsible for the regulation of lipid homeostasis and are crucial [64].

In the high-fat diet (HFD) Sprague-Dawley rat model [65], sesamin administered at dose 160 ppm by weight exhibit a reduced level of steatosis through inhibition of gene tags: *TC* and *TAG* accumulation. Equally, sesamin reversed the effect of HFD to the levels of inflammatory cytokines such as IL-6 and TNF-α. In parallel, sesamin downregulates the LXR-α prompted by HFD, while sesamin upregulates the expression of PPAR-α, which stimulates attenuation in the hepatic fat accumulation.

The life threatening of fulminant hepatic failure (FHF) is described as the immense hepatocyte necrosis and sudden decrease in the liver function. This results to multiple organ disfunction syndromes and hepatic encephalopathy [66,67]. In lipopolysaccharide/d-galactosamine (LPS/d-GalN)-induced FHF mice model [68], 100 ppm of sesamin shows improved mortality and promotes serum aminotransferases activity for 6 h. Moreover, sesamin possess hepatoprotection by reducing the regulation of expression of hepatic *TNF-*α mRNA and protein as well as intercellular adhesion molecule-1 (ICAM-1) and endothelial cell adhesion molecule-1 (ECAM-1). Similarly, sesamin downregulates the expression of TLR4 hindering the MAPK and NF-кB signaling pathway. In one small study, sesamin alleviates the synergistic effect of combined lead (Pb) and LPS causing acute hepatic injury effectively. The suppressive effect of sesamin positively affects several inflammatory signaling pathways such as *COX-2*, *iNOS*, JNK and p38 MAPKs, CHOP and GADD45b [69].

The conversion of sesamin into catechol derivatives and converted further into glucuronides or sulfates in the liver [70–73] has been reported to have anti-inflammatory effect on macrophage cell line (J774.1 cells). The said sesamin metabolites have been reported to have strong inhibitory effects on the LPS-induced NO production [74]. Through methylation, the catechol group of the sesamin metabolites was found to cause this inhibition. Though the level of the inhibitory effect of the sesamin metabolites differs, its inhibitory strength is relative to one another. One of the noticeable interactions is the deconjugation of (7α,7- α,8α,8- α)-3,4-dihydroxy-3- ,4- -methylenedioxy-7,9- :7- ,9-diepoxylignane (SC1) glucuronide to (7α,7- α,8α,8- α)-3-methoxy-4-hydroxy-3- ,4- -methylenedioxy-7,9- :7- ,9-diepoxylignane (SC1m) in macrophages. With this, the time-dependent deconjugation enhances the inhibitory effect against the LPS-induced NO production in macrophages. Correspondingly, the inhibitory effects of SC1 glucuronide are controlled by the β-glucuronidase activity and catechol-*O*-methyltransferase (COMT) activity in macrophages. β-glucuronidase activity hinders the accumulation of SC1m in macrophages and hence, withdraws its inhibitory effect. On the other hand, the COMT activity helps the inhibitory effects of SC1 glucuronide in macrophages. The sulfates of the sesamin metabolites, however, possess weak or non-inhibitory effects towards the LPS-stimulated macrophages. The conversion of sesamin to SC1 during the metabolism of macrophage is therefore the prominent form for the anti-inflammatory effects [75].

Sesame oil, at dosage 1 and 2 ppm, possess protective effect against nutritional steatohepatitis in the methionine-choline deficient (MCD) mice model [76]. Sesame oil with concentration of 4 ppm has been reported to mitigate hepatic injury, α-SMA, fibrosis and reduces the activity of MMP-2, and -9. However, at the same concentration of sesame oil, it elevates the expression of PPAR-γ and tissue inhibitor matrix metalloproteinase 1 (TIMP-1) [77]. It was mentioned, consequently, that consumption of a large dosage of sesame oil might cause steatohepatitis due to suppression of its antioxidative effect [78]. PPAR-γ, when activated, is responsible for suppressing the expression of collagen and inhibition of hepatic fibrosis by blocking the profibrogenic transforming growth factor beta (TGF-β)/Smad pathway which then down-regulates the expression of α-SMA expression [79–81]. MMPs cleave the fibrillar extracellular matrix (ECM) and aid in apoptosis, specifically MMP-2 and -9. As mentioned above, sesame oil inhibits MMP-2 and -9 as it regulates the expression of TIMP-1. This results to alleviating the injury, hepatic stellate cell (HSC) activation and degradation of ECM and utmost is reversing the fibrosis [82]. Conversely, the US Food and Drug Administration's approval for its medication for the treatment of non-alcoholic steatohepatitis (NASH) has not yet been made.

In a different rat model [83], sesame oil has been found to possess preventive expression of proteins in HFD-induced endoplasmic reticulum (ER) stress and to prevent the initiation of apoptosis. Furthermore, sesame oil has been reported to decrease the expression levels of lipogenic transcription factors (by 44.58%) and enzymes in the liver, which also increases the expression of fatty acid oxidation-related gene. Similarly, sesame oil suppresses the regulation of sterol regulatory element-binding protein 1 (SREBP-1) by 22.91% and the expression of FAS by 50.38%, however, it promotes the expression levels of PPAR-α and carnitine palmitoyl transferase 1 (CPT-1). In view of these regulations, this increases the hepatic lipid oxidation and hence prevents hepatic fat accumulation.
