Oleanolic Acid Inhibits SCD1 Gene Expression to Ameliorate Fructose-Induced Hepatosteatosis through SREBP1c-Dependent and -Independent Mechanisms.

SCOPE: The mechanisms of oleanolic acid (OA) regulating hepatic sterol regulatory element-binding protein (SREBP) 1c/stearoyl-CoA desaturase (SCD) 1 pathway to ameliorate fructose-induced hepatosteatosis are investigated. METHODS AND RESULTS: Rats treated with 10% w/v fructose solution are co-administered by OA for 5 weeks, and then sacrifice after fasting for 14 h. OA reverses the fructose-induced increase in hepatic triglyceride (TG) content and downregulates Scd1 mRNA expression. However, two upstream transcription factors, ChREBP and SREBP1c, remain at normal levels with or without fructose and/or OA. In vivo and in vitro studies using SREBP1c-/- mice and HepG2 cell models show that OA also inhibits SCD1 gene overexpression and high hepatic TG levels induced by fructose. On the other hand, in SCD1-/- mice, when the fructose diet is supplemented with high levels of oleic acid (OLA) to compensate for the deficiency of SCD1, OA inhibits hepatic SREBP1c and lipogenic gene expression and reduces hepatic OLA (C18:1) production to improve fructose and/or OLA induced liver lipid deposition. Furthermore, OA promotes PPARα and AMPK to enhance fatty acid oxidation in fructose + OLA-fed SCD1-/- mice. CONCLUSION: OA may inhibit SCD1 gene expression to ameliorate fructose-induced hepatosteatosis through SREBP1c-dependent and -independent mechanisms.

6-Gingerol ameliorates adipose tissue insulin resistance in aging rats / 中国中药杂志

This study investigated the effects and mechanisms of 6-gingerol on adipose tissue insulin resistance in naturally aging rats with glycolipid metabolism disorders. Twenty-seven aging male SD rats were randomly divided into a model group(aged, n=9) and two groups treated with 6-gingerol at 0.05 mg·kg~(-1)(G-L, n=9) and 0.2 mg·kg~(-1)(G-H, n=9). Six young rats were randomly assigned to a normal control group(NC). Rats were treated for seven weeks by gavage. Non-esterified fatty acid(NEFA) and insulin content was determined by enzyme-linked immunosorbent assay(ELISA), and adipose tissue insulin resistance index(Adipo-IR) was calculated. HE staining was used to observe the size of adipocytes in epididymal white adipose tissue(eWAT). The gene and protein expression levels of adiponectin receptor 1(AdipoR1), AMP-activated protein kinase α(AMPKα), phosphorylated AMPK(p-AMPKα~(Thr172)), peroxisome proliferator-activated receptor-γ coactivator-1α(PGC-1α), phosphatidylinositol 3-kinase(PI3 K), protein kinase B(Akt), phosphorylated Akt(p-Akt~(Ser473)), tumor necrosis factor-α(TNF-α), c-Jun N-terminal kinase 1/2(JNK1/2), phosphorylated JNK1/2(p-JNK~(Thr183/Tyr185)), interleukin-1β(IL-1β), and interleukin-6(IL-6) in adiponectin(APN), insulin, and inflammatory factor signaling pathways were detected by Western blot and real-time RCR, respectively. The results showed that 6-gingerol at a high dose could significantly decrease the fasting plasma content of NEFA and insulin and reduce Adipo-IR. Additionally, 6-gingerol at a high dose significantly increased the protein and mRNA expression of APN, AdipoR1, PGC-1α, and PI3 K in eWAT, elevated the relative expression of p-AMPK~(Thr172) and p-Akt~(Ser 473), reduced the protein and mRNA expression of TNF-α, IL-1, and IL-6 in eWAT, and decreased the relative expression of p-JNK1 and p-JNK2. This study reveals that 6-gingerol can improve insulin sensitivity of adipose tissues in aging rats with glycolipid metabolism disorders, and this effect is presumedly achieved by enhancing the PI3 K/Akt signaling pathway, inhibiting adipose tissue inflammation, increasing APN synthesis, enhancing AdipoR1 expression, and activating its downstream AMPK/PGC-1α signaling pathway.

Ursolic acid ameliorates adipose tissue insulin resistance in aged rats via activating the Akt-glucose transporter 4 signaling pathway and inhibiting inflammation.

Ageing often results in insulin resistance (IR) and chronic inflammation, and adipose is one of the tissues in which inflammation and IR occur earliest during this process. The present study investigated the effect and underlying mechanisms of ursolic acid (UA) on adipose IR and inflammation in ageing rats. Specific pathogen-free male Sprague-Dawley rats were randomly divided into 4 groups: i) Young normal (young); ii) untreated ageing (aged); and groups supplemented with UA either iii) low-UA 10 mg/kg (UA-L) or iv) high-50 mg/kg (UA-H). Animals in the UA-treated groups received 10 or 50 mg/kg UA (suspended in 5% Gum Arabic solution). The rats in the corresponding aged group and young groups received vehicle (5% Gum Arabic) alone. All rats were intragastrically treated once daily by oral gavage for 7 weeks. The day before the experiment terminated, overnight fasting blood (~700 µl) was collected and plasma was prepared to measure biochemical indicators; western blotting was performed to analyze the expression of insulin signaling proteins [(insulin receptor substrate 1 (IRS-1), phosphorylated (p)-IRS-1, PI3K, glucose transporter 4 (GLUT4), Akt and p-Akt)] and inflammatory factors (NF-κB, IL-6 and IL-1ß) in the epididymis white adipose tissue (eWAT). The results revealed that treatment with UA-H decreased eWAT weight, the ratio of eWAT weight/body weight, fasted insulin and triglyceride levels, the homeostasis model assessment of insulin resistance and adipose tissue insulin resistance index in ageing rats, indicating the amelioration of systemic and adipose tissue IR, compared with the aged group. Mechanistically, UA-H administration upregulated p-protein kinase B, the ratio of p-Akt to protein kinase B and total and cellular membrane GLUT4 protein levels in eWAT of ageing rats. Conversely, UA inhibited the increase in NF-κB expression and proinflammatory cytokines IL-6 and IL-1ß. However, these alterations were not observed in the rats of the aged group. Taken together, the findings of the present study indicated that UA may ameliorate adipose IR, which is associated with activation of the Akt-GLUT4 signaling pathway and inhibition of inflammation in ageing rats. These data provide a basis for the development of effective and safe drugs or functional substances, such as UA, for the prevention and treatment of metabolic diseases.

Apple pomace and rosemary extract ameliorates hepatic steatosis in fructose-fed rats: Association with enhancing fatty acid oxidation and suppressing inflammation.

Apple pomace and rosemary (AR) have been reported to contain rich bioactive molecules, which have numerous metabolic effects. Our preliminary work revealed that AR ameliorated fructose-induced insulin resistance in rats by modulating sarcolemmal CD36 and glucose transporter-4. The present study aimed to further examine how AR improves metabolic disorders by investigating the effect of AR on hepatic steatosis induced by fructose overconsumption. The results demonstrated that AR (100 mg/kg daily by gavage for 5 weeks) attenuated chronic liquid fructose consumption-induced increases in liver triglyceride content in rats. Mechanistically, reverse transcription-quantitative PCR and western blot analysis results indicated that AR reversed fructose-induced suppression of hepatic peroxisome proliferator-activated receptor α, carnitine palmitoyl-transferase 1α, sirtuin 1 and peroxisome proliferator-activated receptor-γ coactivator 1α, which were associated with the fatty acid oxidative (FAO) pathway. In addition, AR treatment decreased the expression levels of the pro-inflammatory proteins NF-κB and tumor necrosis factor-α. However, AR had no effect on the genes related to lipogenesis and the very low-density lipoprotein-export pathway in rat liver. Thus, the present results suggested that AR treatment diminished long-term fructose overconsumption-induced fatty liver, which was associated with enhanced FAO and suppressed inflammation.

Rhodiola crenulata root extract ameliorates fructose-induced hepatic steatosis in rats: Association with activating autophagy.

BACKGROUND: Increasing evidence has shown the beneficial effects of Rhodiola species on metabolic disorders, but their mechanisms are not clear. Hepatic steatosis is closely related to metabolic disorders, we aim to investigate the therapeutic effects of Rhodiola crenulata root (RCR) on fructose-induced hepatic steatosis and explore the underlying mechanisms. PURPOSE: To observe the effect of Rhodiola crenulata root extract (RCR) on fructose-induced hepatic steatosis in Sprague-Dawley (SD) rats and explore its possible mechanism. METHODS: Male Sprague-Dawley rats were treated with liquid fructose in their drinking water over 18 weeks. The extract of RCR was co-administered (once daily by oral gavage) during the last 5 weeks. Liver lipid deposition and morphological changes were observed by Oil red O staining. Real-time fluorescence quantitative PCR, Western blot and immunoprecipitation were used to detect gene and protein expression in liver. RESULTS: RCR (50 mg/kg) reversed liquid fructose-induced increase in hepatic triglyceride content in rats. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in RCR-treated rats. However, RCR treatment did not affect chow intake and body weight of rats. Although some genes of the pathways involved in DNL (ChREBP, SREBP-1c, FAS, ACC1, SCD1, DGAT1, DGAT2 and MGAT2), fatty acid ß-oxidation (PPARα, CPT1a, ACO and FGF21), VLDL-export (MTTP) and decomposition (HSL, ATGL) in the liver of fructose-fed rats were not changed significantly after RCR administration, the decrease in PPARα and PGC-1α proteins was reversed by RCR. Notably, SIRT1 mRNA and protein expression increased significantly with RCR administration. Furthermore, RCR increased expression of ATG4B, Beclin1 and decreased expression of Bcl2-Beclin1 complex dramatically. Meanwhile, RCR decreased the acetylation of beclin1. Moreover, RCR increased expression of autophagosome markers including LC3B and ATG5-ATG12-ATG16L1, and decreased expression of autophagolysosome marker p62 in the livers of fructose-fed rats. CONCLUSIONS: RCR has a certain improvement effect on fructose-induced hepatic steatosis, which is related to the activation of autophagy.

6-gingerol ameliorates age-related hepatic steatosis: Association with regulating lipogenesis, fatty acid oxidation, oxidative stress and mitochondrial dysfunction.

The prevalence of NAFLD increases with age. As the main active ingredient of ginger, 6-gingerol significantly improves lipid metabolism abnormalities in adult rodents. However, few studies have reported its effect on age-related NAFLD. This study was to investigate the effects of 6-gingerol on age-related hepatic steatosis and its potential targets. As expected, 6-gingerol dramatically normalized the hepatic triglyceride content, plasma insulin and HOMA-IR index of ageing rats. Mechanistically, 6-gingerol affected lipid metabolism by increasing ß-oxidation and decreasing lipogenesis through activation of PPARα and CPT1α and inhibition of DGAT-2. Furthermore, 6-gingerol reversed the decreases in citrate, Cs and ATP, lessened the damage caused by ROS, and upregulated mitochondrial marker enzymes NOX, SDH, and SIRT3 in the ageing liver, indicating its ability to strengthen mitochondrial function. Our results showed 6-gingerol exerted a positive effect on insulin sensitivity by regulating Akt. In conclusion, the hepatic anti-steatotic effect of 6-gingerol is associated with inhibition of de novo lipogenesis, upregulation of fatty acid oxidation, reduction in oxidative stress and synergistic enhancement of mitochondrial function.

6-Gingerol Improves Ectopic Lipid Accumulation, Mitochondrial Dysfunction, and Insulin Resistance in Skeletal Muscle of Ageing Rats: Dual Stimulation of the AMPK/PGC-1α Signaling Pathway via Plasma Adiponectin and Muscular AdipoR1.

SCOPE: This study investigates the dual actions of 6-gingerol in stimulating both plasma adiponectin and muscular adiponectin receptor signaling in naturally ageing rats. METHODS AND RESULTS: Twenty-two-month-old male SD rats were treated with 6-gingerol (0.2 mg kg-1 , once daily) for 7 weeks. 6-Gingerol can attenuate age-associated high plasma triglyceride, glucose, and insulin concentrations under fasting conditions as well as suppress the increase in the HOMA-IR index and inhibit the decrease of muscular p-Akt/Akt protein in ageing rats, which indicates an improvement of systemic and muscular insulin sensitivity. Accompanying these changes, treatment with 6-gingerol attenuates excessive triglyceride accumulation, enhances mitochondrial function, and promotes a transition from a fast- to slow-fiber type and muscle oxidative metabolism in the red gastrocnemius of ageing rats. More importantly, 6-gingerol not only increases the plasma and adipose tissue adiponectin concentrations, but also elevates muscular AdipoR1 expression and activates downstream AMPK phosphorylation as well as upregulates PGC-1α in vivo and in vitro. CONCLUSION: 6-Gingerol may improve ectopic lipid accumulation, mitochondrial dysfunction, and insulin resistance in skeletal muscle of ageing rats. These effects rely, at least in part, on the elevated plasma adiponectin concentration and muscle AdipoR1 level to dually activate the AMPK/PGC-1α signaling pathway.

A mixture of apple pomace and rosemary extract improves fructose consumption-induced insulin resistance in rats: modulation of sarcolemmal CD36 and glucose transporter-4.

Apple pomace is a by-product of the processing of apple for juice, cider or wine preparation. Rosemary is a herb commonly used as spice and flavoring agent in food processing. Evidence suggests that both apple pomace and rosemary have rich bioactive molecules with numerous metabolic effects. To provide more information for using apple pomace and rosemary as functional foods for management of metabolism-associated disorders, the present study investigated the insulin-sensitizing effect of a mixture of apple pomace and rosemary extract (AR). The results showed that treatment with AR (500 mg/kg, daily, by gavage) for 5 weeks attenuated chronic liquid fructose consumption-induced increases in fasting plasma insulin concentration, the homeostasis model assessment of insulin resistance index and the adipose tissue insulin resistance index in rats. Mechanistically, AR suppressed fructose-induced acceleration of the clearance of plasma non-esterified fatty acids during oral glucose tolerance test, and decreased excessive triglyceride accumulation and the increased Oil Red O staining area in the gastrocnemius. Furthermore, AR restored fructose-induced overexpression of sarcolemmal CD36 that is known to contribute to etiology of insulin resistance by facilitating fatty acid uptake, and downregulation of sarcolemmal glucose transporter (GLUT)-4 that is the insulin-responsive glucose transporter. Thus, these results demonstrate that AR improves fructose-induced insulin resistance in rats via modulation of sarcolemmal CD36 and GLUT-4.

Treatment with Rhodiola crenulata root extract ameliorates insulin resistance in fructose-fed rats by modulating sarcolemmal and intracellular fatty acid translocase/CD36 redistribution in skeletal muscle.

BACKGROUND: Rhodiola species have been used for asthenia, depression, fatigue, poor work performance and cardiovascular diseases, all of which may be associated with insulin resistance. To disclose the underlying mechanisms of action, the effect of Rhodiola crenulata root (RCR) on insulin resistance was investigated. METHODS: Male Sprague-Dawley rats were treated with liquid fructose in their drinking water over 18 weeks. The extract of RCR was co-administered (once daily by oral gavage) during the last 5 weeks. The indexes of lipid and glucose homeostasis were determined enzymatically and/or by ELISA. Gene expression was analyzed by Real-time PCR, Western blot and/or confocal immunofluorescence. RESULTS: RCR extract (50 mg/kg) suppressed fructose-induced hyperinsulinemia and the increases in the homeostasis model assessment of insulin resistance index and the adipose tissue insulin resistance index in rats. Additionally, this treatment had a trend to restore the ratios of glucose to insulin and non-esterified fatty acids (NEFA) to insulin. Mechanistically, RCR suppressed fructose-induced acceleration of the clearance of plasma NEFA during oral glucose tolerance test (OGTT), and decreased triglyceride content and Oil Red O staining area in the gastrocnemius. Furthermore, RCR restored fructose-induced sarcolemmal overexpression and intracellular less distribution of fatty acid translocase/CD36 that contributes to etiology of insulin resistance by facilitating fatty acid uptake. CONCLUSION: These results suggest that RCR ameliorates insulin resistance in fructose-fed rats by modulating sarcolemmal and intracellular CD36 redistribution in the skeletal muscle. Our findings may provide a better understanding of the traditional use of Rhodila species.

Mitigation of Insulin Resistance by Mangiferin in a Rat Model of Fructose-Induced Metabolic Syndrome Is Associated with Modulation of CD36 Redistribution in the Skeletal Muscle.

Mangiferin is one of the prominent active components responsible for the antidiabetic property of many traditional herbs, but its underlying mechanisms of action remain unclear. CD36 in skeletal muscle is known to contribute to the etiology of insulin resistance by facilitating fatty acid uptake. This study investigated the effect of mangiferin on insulin resistance. The results showed that treatment of Wistar-Kyoto rats with mangiferin (15 mg/kg, once daily, by oral gavage) for 7 weeks inhibited chronic liquid fructose consumption-induced increases in plasma insulin concentrations at the baseline and during oral glucose tolerance test (OGTT), and the homeostasis model assessment of insulin resistance index. It also suppressed the increases in fasted plasma nonesterified fatty acid (NEFA) concentration and the adipose tissue insulin resistance index. Mechanistically, mangiferin neither affected intakes of fructose and chow, and the increase in epididymal and perirenal fat, nor attenuated fructose-induced hypertension. In contrast, mangiferin attenuated fructose-induced acceleration of plasma NEFA clearance during OGTT, and tended to decrease excessive triglyceride accumulation in gastrocnemius. Immunofluorescence staining and subsequent rating of CD36-expressing fibers in gastrocnemius revealed that mangiferin restored fructose-stimulated sarcolemmal CD36 overexpression and decreased intracellular CD36 distribution. In addition, the effects of mangiferin on the parameters associated with insulin resistance and abnormal fatty acid metabolism were absent in the spontaneously hypertensive rats carrying numerous nonfunctional mutations in the CD36 gene. Thus, these results suggest that mangiferin treatment mitigates insulin resistance in a rat model of fructose-induced metabolic syndrome by modulating sarcolemmal and intracellular CD36 redistribution in the skeletal muscle.

Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver.

Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation.

Ginger extract diminishes chronic fructose consumption-induced kidney injury through suppression of renal overexpression of proinflammatory cytokines in rats.

BACKGROUND: The metabolic syndrome is associated with an increased risk of development and progression of chronic kidney disease. Renal inflammation is well known to play an important role in the initiation and progression of tubulointerstitial injury of the kidneys. Ginger, one of the most commonly used spices and medicinal plants, has been demonstrated to improve diet-induced metabolic abnormalities. However, the efficacy of ginger on the metabolic syndrome-associated kidney injury remains unknown. This study aimed to investigate the impact of ginger on fructose consumption-induced adverse effects in the kidneys. METHODS: The fructose control rats were treated with 10% fructose in drinking water over 5 weeks. The fructose consumption in ginger-treated rats was adjusted to match that of fructose control group. The ethanolic extract of ginger was co-administered (once daily by oral gavage). The indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by Real-Time PCR. RESULTS: In addition to improve hyperinsulinemia and hypertriglyceridemia, supplement with ginger extract (50 mg/kg) attenuated liquid fructose-induced kidney injury as characterized by focal cast formation, slough and dilation of tubular epithelial cells in the cortex of the kidneys in rats. Furthermore, ginger also diminished excessive renal interstitial collagen deposit. By Real-Time PCR, renal gene expression profiles revealed that ginger suppressed fructose-stimulated monocyte chemoattractant protein-1 and its receptor chemokine (C-C motif) receptor-2. In accord, overexpression of two important macrophage accumulation markers CD68 and F4/80 was downregulated. Moreover, overexpressed tumor necrosis factor-alpha, interleukin-6, transforming growth factor-beta1 and plasminogen activator inhibitor (PAI)-1 were downregulated. Ginger treatment also restored the downregulated ratio of urokinase-type plasminogen activator to PAI-1. CONCLUSIONS: The present results suggest that ginger supplement diminishes fructose-induced kidney injury through suppression of renal overexpression of macrophage-associated proinflammatory cytokines in rats. Our findings provide evidence supporting the protective effect of ginger on the metabolic syndrome-associated kidney injury.

Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats.

Oleanolic acid, a triterpenoid contained in more than 1620 plants including various fruits and foodstuffs, has numerous metabolic effects, such as hepatoprotection. However, its underlying mechanisms remain poorly understood. Adipose tissue insulin resistance (Adipo-IR) may contribute to the development and progress of metabolic abnormalities through release of excessive free fatty acids from adipose tissue. This study investigated the effect of oleanolic acid on Adipo-IR. The results showed that supplement with oleanolic acid (25 mg/kg, once daily, by oral gavage) over 10 weeks attenuated liquid fructose-induced increase in plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. Simultaneously, oleanolic acid reversed the increase in the Adipo-IR index and plasma non-esterified fatty acid concentrations during the oral glucose tolerance test assessment. In white adipose tissue, oleanolic acid enhanced mRNA expression of the genes encoding insulin receptor, insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase. At the protein level, oleanolic acid upregulated total IRS-1 expression, suppressed the increased phosphorylated IRS-1 at serine-307, and restored the increased phosphorylated IRS-1 to total IRS-1 ratio. In contrast, phosphorylated Akt to total Akt ratio was increased. Furthermore, oleanolic acid reversed fructose-induced decrease in phosphorylated-Akt/Akt protein to plasma insulin concentration ratio. However, oleanolic acid did not affect IRS-2 mRNA expression. Therefore, these results suggest that oleanolic acid supplement ameliorates fructose-induced Adipo-IR in rats via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway. Our findings may provide new insights into the mechanisms of metabolic actions of oleanolic acid.

Modulation of hepatic sterol regulatory element-binding protein-1c-mediated gene expression contributes to Salacia oblonga root-elicited improvement of fructose-induced fatty liver in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Salacia oblonga root (SOR) is a traditionally herbal medicine for obesity and diabetes, which are closely associated with fatty liver. To investigate the molecular mechanisms of SOR in the treatment of dietary-induced fatty liver. MATERIALS AND METHODS: Male rats were co-administered with fructose in drinking water and vehicle or the aqueous-ethanolic extract of SOR (by gavage, once daily) for 10 weeks. Biochemical variables were determined enzymatically or by ELISA. Gene expression was analyzed by Real-Time PCR and/or Western blot. RESULTS: SOR treatment (20mg/kg) diminished fructose-induced fatty liver indicated by decreases in excess triglyceride accumulation and the increased vacuolization and Oil Red O staining area in the livers of rats. Importantly, Hepatic gene expression profile revealed that SOR suppressed fructose-stimulated overexpression of sterol regulatory element-binding protein (SREBP)-1/1c mRNA and nuclear protein. In accord, overexpression of SREBP-1c-responsive genes, such as fatty acid synthase, acetyl-CoA carboxylase-1 and stearoyl-CoA desaturase-1, was also downregulated. In contrast, overexpressed nuclear protein of carbohydrate response element binding protein and mRNA of its target gene liver pyruvate kinase were not altered. Additionally, SOR also did not affect expression of peroxisome proliferator-activated receptor-gamma- and -alpha, as well as their target genes, such as carnitine palmitoyltransferase-1a, acyl-CoA oxidase and CD36. CONCLUSIONS: These results suggest that modulation of hepatic sterol regulatory element-binding protein-1c-mediated gene expression contributes to SOR-elicited improvement of fructose-induced fatty liver in rats. Our findings provide a better understanding of SOR in the treatment of obesity and diabetes.

Oleanolic Acid diminishes liquid fructose-induced Fatty liver in rats: role of modulation of hepatic sterol regulatory element-binding protein-1c-mediated expression of genes responsible for de novo Fatty Acid synthesis.

Oleanolic acid (OA), contained in more than 1620 plants and as an aglycone precursor for naturally occurred and synthesized triterpenoid saponins, is used in China for liver disorders in humans. However, the underlying liver-protecting mechanisms remain largely unknown. Here, we found that treatment of rats with OA (25 mg/kg/day, gavage, once daily) over 10 weeks diminished liquid fructose-induced excess hepatic triglyceride accumulation without effect on total energy intake. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in OA-treated rats. Hepatic gene expression profile demonstrated that OA suppressed fructose-stimulated overexpression of sterol regulatory element-binding protein-(SREBP-) 1/1c mRNA and nuclear protein. In accord, overexpression of SREBP-1c-responsive genes responsible for fatty acid synthesis was also downregulated. In contrast, overexpressed nuclear protein of carbohydrate response element-binding protein and its target genes liver pyruvate kinase and microsomal triglyceride transfer protein were not altered. Additionally, OA did not affect expression of peroxisome proliferator-activated receptor-gamma- and -alpha and their target genes. It is concluded that modulation of hepatic SREBP-1c-mediated expression of the genes responsible for de novo fatty acid synthesis plays a pivotal role in OA-elicited diminishment of fructose-induced fatty liver in rats.

Improvement of liquid fructose-induced adipose tissue insulin resistance by ginger treatment in rats is associated with suppression of adipose macrophage-related proinflammatory cytokines.

Adipose tissue insulin resistance (Adipo-IR) results in excessive release of free fatty acids from adipose tissue, which plays a key role in the development of "lipotoxicity." Therefore, amelioration of Adipo-IR may benefit the treatment of other metabolic abnormalities. Here we found that treatment with the alcoholic extract of ginger (50 mg/kg/day, by oral gavage) for five weeks attenuated liquid fructose-induced hyperinsulinemia and an increase in the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. More importantly, ginger reversed the increases in the Adipo-IR index and plasma nonesterified fatty acid concentrations during the oral glucose tolerance test assessment. Adipose gene/protein expression profiles revealed that ginger treatment suppressed CD68 and F4/80, two important macrophage accumulation markers. Consistently, the macrophage-associated cytokines tissue necrosis factor alpha and interleukin-6 were also downregulated. In contrast, insulin receptor substrate (IRS)-1, but not IRS-2, was upregulated. Moreover, monocyte chemotactic protein (MCP)-1 and its receptor chemokine (C-C motif) receptor-2 were also suppressed. Thus these results suggest that amelioration of fructose-induced Adipo-IR by ginger treatment in rats is associated with suppression of adipose macrophage-related proinflammatory cytokines.

Treatment with ginger ameliorates fructose-induced Fatty liver and hypertriglyceridemia in rats: modulation of the hepatic carbohydrate response element-binding protein-mediated pathway.

Ginger has been demonstrated to improve lipid derangements. However, its underlying triglyceride-lowering mechanisms remain unclear. Fructose overconsumption is associated with increase in hepatic de novo lipogenesis, thereby resulting in lipid derangements. Here we found that coadministration of the alcoholic extract of ginger (50 mg/kg/day, oral gavage, once daily) over 5 weeks reversed liquid fructose-induced increase in plasma triglyceride and glucose concentrations and hepatic triglyceride content in rats. Plasma nonesterified fatty acid concentration was also decreased. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in ginger-treated rats. However, ginger treatment did not affect chow intake and body weight. Further, ginger treatment suppressed fructose-stimulated overexpression of carbohydrate response element-binding protein (ChREBP) at the mRNA and protein levels in the liver. Consequently, hepatic expression of the ChREBP-targeted lipogenic genes responsible for fatty acid biosynthesis was also downregulated. In contrast, expression of neither peroxisome proliferator-activated receptor- (PPAR-) alpha and its downstream genes, nor PPAR-gamma and sterol regulatory element-binding protein 1c was altered. Thus the present findings suggest that in rats, amelioration of fructose-induced fatty liver and hypertriglyceridemia by ginger treatment involves modulation of the hepatic ChREBP-mediated pathway.

Rhodiola crenulata root ameliorates derangements of glucose and lipid metabolism in a rat model of the metabolic syndrome and type 2 diabetes.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhodiola species are traditionally used as tonics and stimulants to treat asthenia, suggesting their possible regulatory effect on energy metabolism. Clinical trials have demonstrated their glucose-lowering effect in type 2 diabetes. AIM OF THE STUDY: To examine the effects of Rhodiola on glucose and lipid metabolism in the metabolic syndrome and type 2 diabetes. MATERIALS AND METHODS: Zucker diabetic fatty (ZDF) rats were treated with Rhodiola crenulata root (RCR) powder (100 and 500 mg/kg, by gavage, once daily for 4 weeks). In addition, the effects of RCR on sucrose-induced acute hyperglycemia in mice and olive oil-induced hypertriglyceridemia in rats were also examined. Biochemical variables were determined enzymatically or by ELISA. RESULTS: In ZDF rats, RCR treatment decreased the increased plasma insulin and triglyceride concentrations at baseline, the index of the homeostasis model assessment of insulin resistance (HOMA-IR) and excessive hepatic triglyceride accumulation. This treatment also inhibited abnormal increases in plasma glucose and insulin concentrations during oral glucose tolerance test. Furthermore, RCR reversed the increased adipose insulin resistance index, and accelerated the decline of plasma concentrations of non-esterified fatty acids after exogenous glucose stimulation. However, RCR minimally affected sucrose-induced acute hyperglycemia in mice and olive oil-induced acute hypertriglyceridemia in rats. CONCLUSIONS: The present results demonstrate that RCR treatment improves metabolic derangements in animal model of the metabolic syndrome and type 2 diabetes. Our findings may provide new pharmacological basis of therapeutics for the adaptogenic plants to treat metabolic derangements-associated disorders, such as asthenia.

Salacia oblonga ameliorates hypertriglyceridemia and excessive ectopic fat accumulation in laying hens.

ETHNOPHARMACOLOGICAL RELEVANCE: Salacia oblonga root (SOR) is an Ayurvedic medicine for obesity and diabetes, those are associated with glucose and lipid metabolism. AIM OF THE STUDY: SOR has been demonstrated previously to improve glucose and lipid metabolism in animal models of obesity and diabetes and to be a peroxisome proliferator-activated receptor-alpha activator. However, the anti-obesogenic and anti-diabetic mechanisms of SOR are still not largely understood. Here, we investigated the effects of SOR on lipid metabolism using laying hen, a unique animal model with a very high rate of triglyceride synthesis in the liver. MATERIALS AND METHODS: Laying hens and preadolescent pullets were treated with the layer ration containing 0%, 0.5%, or 1% SOR water extract for 4 weeks. Biochemical variables were determined enzymatically. RESULTS: Laying hens showed much higher fasted triglyceride concentrations (increased by 5-13 folds) in plasma, liver, skeletal muscle and heart than pullets. 1% SOR extract treatment inhibited body weight increase without affecting food intake. Importantly, this treatment substantially attenuated hypertriglyceridemia and inhibited increases in triglyceride contents in the non-adipose tissues. However, SOR extract did not induce change in plasma glucose concentration. Moreover, SOR extract did not alter all variables in pullets. CONCLUSIONS: These results demonstrate that SOR ameliorates hypertriglyceridemia and excessive ectopic fat accumulation in laying hens. These findings suggest that the triglyceride-lowering property is one of the primary effects of SOR, possibly via hepatic mechanisms.

55-week treatment of mice with the unani and ayurvedic medicine pomegranate flower ameliorates ageing-associated insulin resistance and skin abnormalities.

PPARs play a pivotal role in regulating lipid and glucose homeostasis and are involved in diverse biological activities in skin. Pomegranate flower (PGF, an antidiabetic therapy in Unani and Ayurvedic medicines) has been previously demonstrated to activate both PPARalpha/gamma. Here, we found that treatment of mice with the diet containing PGF powder over 55 weeks attenuated ageing-induced abnormal increases in the homeostasis model assessment of insulin resistance, glucose concentrations during oral glucose tolerance test, and adipose insulin resistance index. The diet tended to decrease the excessive peri-ovary fat mass. It, however, increased the thinned subcutaneous fat thickness. In addition, the diet restored decreases in skin water content, epidermis thickness, and collagen density in corium. Thus, our results demonstrate that long-term treatment with the Unani and Ayurvedic therapy ameliorates ageing-induced insulin resistance, which is associated with reversal of ageing-induced fat redistribution. Further, PGF attenuates ageing-mediated undesirable skin abnormalities.