Effects of combined PPAR-γ and PPAR-α agonist therapy on fructose induced NASH in rats: Modulation of gene expression

El-Haleim, Enas A Abd; Bahgat, A.; Saleh, S. A.

doi:10.1016/j.ejphar.2016.01.011

Cited by 28 publications

(19 citation statements)

References 64 publications

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“…These results are in agreement with those of Abd El-Haleim et al (36) and also indicate that treatment with TZD has a significant role on the serum lipid profile, as suggested by Wang et al (37). However, it has been previously reported that TZD administration may lead to deteriorating microvesicular steatosis and raised hepatic TG levels, through decreasing blood TG and free fatty acid (23).…”

Section: Discussionsupporting

confidence: 93%

Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl‑CoA desaturase‑1, lipase activity, leptin and resistin

Al‐Muzafar

Amin

2018

Exp Ther Med

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Hepatosteatosis is a disease present worldwide, which presents a number of health problems. Recently, thiazolidinedione (TZD) has been used as a therapy for lipid disorders. The present study demonstrates the potential of TZD as a treatment for hepatosteatosis and its mechanism of action, particularly focusing on its role in lipid metabolism. A total of 60 (80–90 g) rats were divided into three groups: A normal group with a standard diet, a high-fat, high-carbohydrate diet (HFCD) group or a HFCD+TZD group (n=20/group). The HFCD induced hepatosteatosis over a period of 12 weeks and the HFCD+TZD group were administered TZD in weeks 13–16. Blood and tissue samples were collected to measure hepatic function, the lipid profile, metabolism and hormone biomarkers, including serum triglyceride (TG), lipoprotein lipase (LPL), stearoyl-CoA desaturase (SCD-1), leptin and resistin. The HFCD-fed rats exhibited a significant increase in serum TG, total cholesterol, low-density lipoproteins, alanine transaminase and bilirubin compared with the normal group as well as a significant decrease in high-density lipoprotein. In addition, serum leptin and resistin were significantly elevated in the HFCD group compared with the normal group. The administration of TZD significantly increased SCD-1 activity and significantly inhibited LPL activity. It also attenuated the changes in the lipid profiles and normalized serum leptin and resistin levels. The results of the present study indicated that HFCD induced lipid abnormalities associated with hypertriglyceridemia, hypercholesterolemia and hepatosteatosis. These changes resulted from disruption to leptin and resistin, which may be due to alterations in LPL and SCD-1 activity. TZD mitigated the effects of HFCD-induced hepatosteatosis, indicating a possible regulatory effect of TZD in the development of hepatosteatosis. The authors suggest that the manipulation of SCD-1 and lipase by TZD may be useful as a treatment for hepatosteatosis.

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Section: Discussionsupporting

confidence: 93%

Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl‑CoA desaturase‑1, lipase activity, leptin and resistin

Al‐Muzafar

Amin

2018

Exp Ther Med

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“…Compatible with the above findings regarding the effects of FF and PG, it had previously been shown that the treatment with both drugs improved nonalcoholic steatohepatitis-related disturbances in serum glucose, insulin, and TG by modulating hepatic and adipose tissue expression of genes responsible for IR and fatty acid synthesis in rats given 10% Fr in drinking water for 12 weeks [57]. With this low concentration of Fr, pronounced alterations commonly associated with the metabolic syndrome, such as hyperuricemia, hypercholesterolemia, and changes in hepatic antioxidant defense mechanisms, may be absent [23, 58, 59].…”

Section: Discussionmentioning

confidence: 99%

Amelioration of High Fructose Diet-Induced Insulin Resistance, Hyperuricemia, and Liver Oxidative Stress by Combined Use of Selective Agonists of PPAR-α and PPAR-γ in Rats

Farag¹,

Ashour²,

El-Hadidy³

2020

Dubai Med J

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Background: The use of high-fructose (Fr) corn sweeteners and sucrose in manufactured food has markedly increased recently. This excessive Fr intake has been proposed in the etiology of the metabolic syndrome, which shows an increasing prevalence throughout the world. Objective: In this study, we questioned whether fenofibrate (FF), a peroxisome proliferator-activated receptor (PPAR)-α agonist, and pioglitazone (PG), a PPAR-γ agonist, might be effective in ameliorating the metabolic syndrome in a rat model. Materials and Methods: The metabolic syndrome was induced by feeding rats a high-Fr (60%) diet for 10 weeks. The rats were divided into 5 groups: control group, fed a normal rat chow; Fr + vehicle group; Fr + FF group; Fr + PG group; and Fr + (FF + PG) group (treated with both drugs). Drug or vehicle treatment was given daily for 6 weeks (from weeks 5 to 10). Thereafter, blood and liver samples were obtained for biochemical studies. Results: Rats fed a high-Fr diet developed hyperglycemia, hyperinsulinemia, hyperuricemia, hypertriglyceri demia, and hypercholesterolemia, and had increased serum alanine aminotransferase, hepatic tumor necrosis factor-α, and malondialdehyde levels but decreases in both glutathione content and superoxide dismutase activity. Rat treatment with FF and/or PG attenuated these alterations. The improvement was greater with the combined treatment than with either drug alone, and normalization of insulin sensitivity was observed only in rats treated with the combination therapy. Conclusion: Acting on the 2 main PPAR subfamilies, the combination of FF and PG provides a more efficacious therapy for modulating the changes in serum insulin, uric acid, and lipids, as well as the accompanying hepatic inflammation and oxidative stress that characterize the Fr-induced metabolic syndrome.

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“…SOD is an important antioxidant biomarker by detoxifying normally generated reactive oxygen species. The increase of PPAR-α will enhance antioxidant functions of liver cells by affecting the level of SOD, ALT and AST [13,72]. In contrast, SREBP-1c will increase the level of ROS in hepatocytes and aggravate inflammatory injury of liver tissues [73].…”

Section: Discussionmentioning

confidence: 99%

“…Drug therapy is still the main option to control NASH progression [8,9,10]. The common drugs for NASH treatment are vitamin E [11], pioglitazone [12], peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ agonist [13], etc. Vitamin E has antioxidant activities and is widely used for treating chronic liver disorders.…”

Section: Introductionmentioning

confidence: 99%

“…Pioglitazone shows inhibitory effects on the level of vascular endothelial growth factor (VEGF), which is related to many ischemic and inflammatory disorders, and the main factor contributing to the progression of liver fibrosis and hepatic carcinogenesis [15]. The activation of PPAR-α and PPAR-γ ameliorates NASH by regulating the gene expression in hepatic and adipose tissues [13]. However, all these medicines have obvious side effects.…”

Section: Introductionmentioning

confidence: 99%

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The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α

Ren

Zhu

et al. 2017

Nutrients

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Nonalcoholic steatohepatitis (NASH) is liver inflammation and a major threat to public health. Several pharmaceutical agents have been used for NASH therapy but their high-rate side effects limit the use. Blueberry juice and probiotics (BP) have anti-inflammation and antibacterial properties, and may be potential candidates for NASH therapy. To understand the molecular mechanism, Sprague Dawley rats were used to create NASH models and received different treatments. Liver tissues were examined using HE (hematoxylin and eosin) and ORO (Oil Red O) stain, and serum biochemical indices were measured. The levels of peroxisome proliferators-activated receptor (PPAR)-α, sterol regulatory element binding protein-1c (SREBP-1c), Patatin-like phospholipase domain-containing protein 3 (PNPLA-3), inflammatory cytokines and apoptosis biomarkers in liver tissues were measured by qRT-PCR and Western blot. HE and ORO analysis indicated that the hepatocytes were seriously damaged with more and larger lipid droplets in NASH models while BP reduced the number and size of lipid droplets (p < 0.05). Meanwhile, BP increased the levels of SOD (superoxide dismutase), GSH (reduced glutathione) and HDL-C (high-density lipoprotein cholesterol), and reduced the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglycerides), LDL-C (low-density lipoprotein cholesterol) and MDA (malondialdehyde) in NASH models (p < 0.05). BP increased the level of PPAR-α (Peroxisome proliferator-activated receptor α), and reduced the levels of SREBP-1c (sterol regulatory element binding protein-1c) and PNPLA-3 (Patatin-like phospholipase domain-containing protein 3) (p < 0.05). BP reduced hepatic inflammation and apoptosis by affecting IL-6 (interleukin 6), TNF-α (Tumor necrosis factor α), caspase-3 and Bcl-2 in NASH models. Furthermore, PPAR-α inhibitor increased the level of SREBP-1c and PNPLA-3. Therefore, BP prevents NASH progression by affecting SREBP-1c/PNPLA-3 pathway via PPAR-α.

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Effects of combined PPAR-γ and PPAR-α agonist therapy on fructose induced NASH in rats: Modulation of gene expression

Cited by 28 publications

References 64 publications

Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl‑CoA desaturase‑1, lipase activity, leptin and resistin

Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl‑CoA desaturase‑1, lipase activity, leptin and resistin

Amelioration of High Fructose Diet-Induced Insulin Resistance, Hyperuricemia, and Liver Oxidative Stress by Combined Use of Selective Agonists of PPAR-α and PPAR-γ in Rats

The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α

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