The high content of saturated fatty acids and fructose in the diet enhanced lipogenesis and insulin-signaling suppression. Furthermore, chronic intake of fructose is correlated with various signs of liver damage, as increased lipid peroxidation, oxidative stress, inflammation, insulin resistance in various tissues, and cellular necrosis. The extensive flow of fructose in the liver prompts a metabolic injury to its tissue [33].
In the current investigation, rats fed on high-fructose–high-fat diet (HFHF) for 16 weeks which is a well-established model for the induction of NAFLD [3]. The data reported in this study revealed that HFHF caused elevation in blood glucose, hypoinsulinemia, hyperlipidemia, and elevation of oxidative stress parameters.
The consumption of fructose molecules is rapidly absorbed through the glucose transporter-5 (GLUT5) and then absorbed by GLUT2 in the liver cells. In contrast, fructose actually cannot be absorbed by pancreatic beta cells due to the extremely low affinity of the pancreatic beta-cell for fructose, so fructose is unable to stimulate insulin secretion [34]. This finding is consistent with Basaranoglu et al. [35], which found that fructose consumption reduced plasma insulin by 24 h but elevated fasting glucose. In addition, Huang et al. [36] pointed out that a high-fructose diet may induce hypoinsulinemia, while a high-fat diet may alter the pancreatic function of insulin secretion and glucose intolerance, stating that the HFHF diet can have diverging effects on glucose metabolism in the rat.
Due to the severe side effects of pharmacologic agents, researchers are trying to use herbal extracts that have lower toxicity than chemical drugs in the treatment of various diseases.
Silymarin, a derivative of milk thistle (Silybum marianum), has been used for centuries as a natural cure for liver and bile duct disease. Consider the therapeutic potential of silymarin on hepatic steatosis with a high-fat diet (HFD)-induced non-alcoholic hepatic steatosis [37], and it is used in this study as a reference drug.
Apium graveolens has different therapeutic properties such as anti-diabetic, anti-inflammatory activity, and antioxidant properties [5]. Flavonoids are among the secondary metabolites of compounds plant that cannot be synthesized by the human body and must be received through diet. Various plants, due to their phenolic content, are believed to enroll in the healing process of free-radical-mediated diseases; celery is among the plants that are rich in flavonoids such as apigenin, luteolin, and apiin [14].
In the recent study, serum glucose level in group receiving Apium seed extract indicated the efficacy in lowering blood glucose levels. The hypoglycemic impact of Apium seed may be due to enhanced secretion of insulin, proliferation, and repair of b-cells from free radical induced damage, increased glucose transport into cells and its utilization by tissues, increased glycogen synthesis from glucose in the liver, and improved oxidant–antioxidant balance [38].
Most of the administered fructose was converted rapidly into glucose by the liver [39]. Part of glucose reduced to sorbitol with aldose reductase, which cannot cross the cell membranes, and accumulated in cells. The increased accumulation of sorbitol and fructose in the rats maintained on a fructose-rich diet affects blood glucose level [40]. Therefore, apigenin and luteolin in celery seed can inhibit aldose reductase enzyme (the enzyme that catalyzes the reduction of glucose to sorbitol in the polyol pathway) [38].
On the other hand, curcumin is a polyphenol isolated from Curcuma longa which has been used as a potential therapeutic agent in some pathological conditions and against many diseases such as sepsis, hepatotoxicity, and neurotoxicity. In this concern, previous studies reported that administration of Curcuma longa improves blood glucose, insulin levels, and insulin resistance through several mechanisms that include the increased activity of glucokinase (GK) and glycogen content in the liver, the activation of glycolytic enzymes, and regulated the gluconeogenic enzymes by inhibition of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities. Indirectly, curcumin diminishes free fatty acids in the liver and so lowers the stimulating of glucose production by liver [41].
In this study, HFHF caused liver damage and demonstrated considerable alternation in serum activity of liver enzymes. Moreover, Lemus-Conejo et al. [42] suggested that HFD-induced obese mice promotes a NAFLD which resulted in elevation in the activities of transaminases. Our study showed administration of celery-restrained GPT and GOT levels in serum as well as lysosomal enzymes in rats challenged by high-fructose–high-fat diet, which implies the repressed damage of liver cells and restoration of the cell membrane function. This may be reverted to its apigenin and lutein content which showed hepatoprotection, anti-oxidant, and anti-inflammatory [40]. Curcumin supplementation with HFHF diet decreased the GPT and GOT levels, so it acts as hepatoprotective prevented fructose-induced hepatotoxicity, leading to reducing the hepatic injury [43].
High-fructose–high-fat diet induces dyslipidemia, as excessive absorption of fatty acids in cells now has three different ways to get rid of: A portion of triglyceride deposition in hepatocytes, leading to NAFLD. Another part binds to apolipoprotein (ApoB) to produce VLDL; or part of them simply diffuse as free fatty acids in the blood circulation and trigger high cholesterol and dyslipidemia [44].
The data reported in this study showed significant elevation in S.CH, S.TG, and LDL and a remarked decrease in HDL in group administered with high fructose in concurrent with high-fat diet.
Due to primary metabolism of fructose in the liver, it may induce NAFLD by its ability to up-regulate de novo lipogenesis (DNL) and by bypassing the major rate-limiting step of glycolysis at phosphofructokinase. Fructose-induced DNL generates fatty acids that can then be incorporated into hepatic TGs or other lipid species. Fructose feeding has also been shown to induce the activation of carbohydrate-responsive element-binding protein and increase the expression of lipogenic genes such as fatty acid synthase, acyl coenzyme-A carboxylase and stearoyl-coenzyme A desaturase-1 in the fructose-fed rat [45].
This study indicates that celery extract markedly declined levels of S.CH, S.TG, and LDL, while elevated HDL. The phytochemical examination of A. graveolens indicated the presence of tannin, terpenoid, alkaloid, flavonoid, glycosides, and sterols, which may be responsible for its hypolipidemic activities. The mechanisms suggested for lipid-lowering action of Apium are inhibition of hepatic cholesterol biosynthesis, increasing fecal bile acid excretion, and enhancing plasma lecithin: cholesterol acyltransferase activity and reduction of lipid absorption in the intestine [46]. On the other hand, blood lipids lowering impact was attributed to the compound 3n butylphthalideor (3nB) isolated from Apium graveolens; this results in agreement with the study of Iyer et al. [46]. In the recent study, curcumin supplementation to rats fed on HFHF diet reported significant lower levels of S.TC, S.TG, and LDL levels, but significant higher level of HDL regarding HFHF group. Our findings were in line with Abdel-Sattar et al. [47] who found the same results in fructose-fed rats with curcumin.
Previous study reported that curcumin enhances lipolysis and β-oxidation by up-regulating the expression of lipases such as adipose triglyceride lipase, hormone-sensitive lipase, adiponectin, and AMP-activated protein kinase [48]. In the same respect, curcumin stimulates the activity of hepatic cholesterol-7α-hydroxylase activity which promotes cholesterol catabolism [49].
Moreover, the progression of non-alcoholic steatosis to steatohepatitis has been linked to the action of reactive oxygen species (ROS) in the liver. ROS lead to an increase in lipid peroxidation, damage of unsaturated lipids in cell membrane, and reduction in endogenous antioxidants, leading to liver tissue injury [50]. Moreover, fructose feeding has been shown to elevated oxidative stress and is associated with metabolic syndromes in rodents, as reviewed previously [51]. This agrees with our results which report that hepatic MDA was raised in rats fed on the HFHFD, indicating lipid peroxidation and the reduction in GSH as antioxidant.
Apium graveolens seed extract showed antioxidant activity represented by MDA reduction in addition to elevation of GSH level due to the presence of flavonoids, tannins, saponins, and luteolin [5]. Moreover, celery contains vitamin C that is a known booster of the immune system and reduces free radicals in the body [15]. The outcomes of the current study on the impact of celery seed extract on the oxidative stress parameters and DNA injury could potentially be due to the presence of sugar or secondary chains of amino acids (S) compounds.
Supplementation of curcumin reduced oxidative stress as it markedly diminishes hepatic MDA, while raised hepatic GSH in the curcumin–HFHF group in comparison with HFHF group. The MDA depletion and oxidative stress attenuation of curcumin may be through scavenging of superoxide anion (O2), hydrogen peroxide (H2O2), hydroxyl radical (HO•), and peroxyl radical (ROO•), and the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2), known as the master regulator of the endogenous antioxidant response, and downstream antioxidant genes. Therefore, the antioxidant property of curcumin helps in scavenging free radicals generated in various conditions associated with metabolic derangements [52].
DNA strand breaks when ROS interact with DNA and play an important role in initiation of apoptosis, which caused fragmented DNA pattern as detected by gel electrophoresis of liver tissue. The major lysosomal enzymes according to their importance as liver injury markers are: acid phosphatase (ACP), β-galactosidase, and N-acetyl-B-glucosaminidase [53]. In many pathological conditions, the loss of the stability of the lysosomal membrane takes place and then leakage of enzymes from lysosomes occurs. ACP is regarded as a hepatic lysosomes enzyme marker for measurement of cell viability, and the other lysosomal enzymes β-GAL, β-NAG, and β-GLU are highly important for liver lysosomal functions [54]. Abdel-Hamid et al. [55] investigated that lysosomal enzymes disorders contribute to several human diseases. A reduction in lysosomal stability is usually accompanied by an increase in lysosomal enzymatic activity in the extracellular fluid.
On the other hands, histopathological examination indicated the development of liver steatosis after HFHF administration; these data are in agreement with Kohli et al. [56]. However, curcumin-treated group showed hepatic injury improvement due to its antioxidant, anti-inflammatory, and hepatoprotective impact as reported by Abdelrazek and Haredy [57]. Further, histopathological results of celery treatment group supported the improvement reported in biochemical examinations by showing normal architecture almost similar to control as reported previously by Cho BO et al. [14].
