High-fat High-fructose Diet Research Articles

Protective Role of Picralima nitida Seed Extract in High-Fat High-Fructose-Fed Rats.

Picralima nitida is a therapeutic herb used in ethnomedicine for the management of several disease conditions including diabetes. This study examined the potential palliative effect of aqueous seed extract of Picralima nitida (APN) on dyslipidemia, hyperglycemia, oxidative stress, insulin resistance, and the expression of some metabolic genes in high-fat high-fructose-fed rats. Experimental rats (2 months old) were fed a control diet or a high-fat diet with 25% fructose (HFHF diet) in their drinking water for nine weeks. APN was administered orally during the last four weeks. Anthropometric and antioxidant parameters, lipid profile, plasma glucose, and insulin levels and the relative expression of some metabolic genes were assessed. APN caused a significant decrease (P < 0.05) in weight gained, body mass index, insulin resistance, plasma glucose, and insulin levels. High-density lipoprotein cholesterol level was significantly increased (P < 0.05), while triacylglycerol, cholesterol, low-density lipoprotein, cardiac index, atherogenic index, coronary artery index, and malondialdehyde levels in plasma and liver samples were also significantly decreased (P < 0.05) by APN at all experimental doses when compared to the group fed with an HFHF diet only. APN also significantly (P < 0.05) upregulated the relative expression of glucokinase, carnitine palmitoyltransferase-1 (CPT-1), and leptin at 400 mg/kg body weight when compared to the group fed with an HFHF diet only. This study showed that APN alleviated dyslipidemia, hyperglycemia, and oxidant effect associated with the intake of a high-fat high-fructose diet.

Susceptibility of Rat Steatotic Liver to Ischemia-Reperfusion Is Treatable With Liver-Selective Matrix Metalloproteinase Inhibition.

This study examined whether enhanced susceptibility of steatotic liver to ischemia-reperfusion (I/R) injury is due to impaired recruitment of bone marrow (BM) progenitors of liver sinusoidal endothelial cells (LSECs, also called sinusoidal endothelial cell progenitor cells [sprocs]) with diminished repair of injured LSECs and whether restoring signaling to recruit BM sprocs reduces I/R injury. Hepatic vessels were clamped for 1hour in rats fed a high-fat, high-fructose (HFHF) diet for 5, 10, or 15weeks. Matrix metalloproteinase 9 (MMP-9) antisense oligonucleotides (ASO) or an MMP inhibitor were used to induce liver-selective MMP-9 inhibition. HFHF rats had mild, moderate, and severe steatosis, respectively, at 5, 10, and 15weeks. I/R injury was enhanced in HFHF rats; this was accompanied by complete absence of hepatic vascular endothelial growth factor (VEGF)-stromal cell-derived factor 1 (sdf1) signaling, leading to lack of BM sproc recruitment. Liver-selective MMP-9 inhibition to protect against proteolytic cleavage of hepatic VEGF using either MMP-9 ASO or intraportal MMP inhibitor in 5-week and 10-week HFHF rats enhanced hepatic VEGF-sdf1 signaling, increased BM sproc recruitment, and reduced alanine aminotransferase (ALT) by 92% and 77% at 5weeks and by 80% and 64% at 10weeks of the HFHF diet, respectively. After I/R injury in 15-week HFHF rats, the MMP inhibitor reduced active MMP-9 expression by 97%, ameliorated histologic evidence of injury, and reduced ALT by 58%, which is comparable to control rats sustaining I/R injury. Rescue therapy with intraportal MMP inhibitor, given after ischemia, in the 5-week HFHF rat reduced ALT by 71% and reduced necrosis. Lack of signaling to recruit BM sprocs that repair injured LSECs renders steatotic liver more susceptible to I/R injury. Liver-selective MMP-9 inhibition enhances VEGF-sdf1 signaling and recruitment of BM sprocs, which markedly protects against I/R injury, even in severely steatotic rats.

Role of polar extracts from two quinoa varieties in prevention of steatohepatitis and cardiovascular diseases and improving glucose tolerance in rats.

Introduction: Steatohepatitis, which is the deposition of fat in the liver with inflammation and starting of necrosis, can induce cardiovascular diseases (CVDs). The aim of this research was to study the preventive effects of steatohepatitis and CVD by ethanol extract of two quinoa varieties (quinoa 1 and hualhuas) in rats. Methods: Phenolic and flavonoid compounds were determined in the extracts utilizing colorimetric and high-performance liquid chromatography techniques. The 2,2-diphenyl-1-picryl-hydrazil (DPPH) scavenging activity was assessed for the extracts. Rats were divided into four groups, the first group was fed on a balanced diet (negative control), and other groups consumed a high fructose-fat diet (HFFD) to induce steatohepatitis and CVD. The second group served as a positive control; however, the third and fourth groups were treated by ethanol extract of quinoa 1 and hualhuas, respectively. Different biochemical changes, as well as liver and heart histopathology, were followed. Results: Results showed significant elevation in liver lipids, plasma malondialdehyde, total cholesterol (T-C), triglycerides and low-density lipoprotein cholesterol with reduction of high-density lipoprotein cholesterol (HDL-C) and total antioxidant as well as a significant increase in T-C/HDL-C in control positive group (P &lt; 0.05) compared to control negative group. Plasma parameters and liver lipids were improved by the extracts; hualhuas was superior concerning the effect on lipid while quinoa 1 was more efficient in reducing oxidative stress. The oral glucose tolerance curve and the histopathology of the liver and heart tissues were improved by both extracts. Total phenolic and DPPH scavenging activity were higher in quinoa 1 than hualhuas. Protocatechuic and rutin were the major identified phenolic acid and flavonoid compounds, respectively in the extracts. Conclusion: Quinoa extracts are able to prevent the progression of steatohepatitis and CVD, and might be beneficial in patients with such diseases.

Nicotinamide and ascorbic acid nanoparticles against the hepatic insult induced in rats by high fat high fructose diet: A comparative study

AimsNon-alcoholic fatty liver disease (NAFLD) caused by consumption of high levels of fat and sugars (HFHS) in diet is considered one of the most dangerous medical complications among children and adolescents. Nicotinamide is among the promising candidates in ameliorating HFHS diet-induced NAFLD, but its use is limited by the possibility of prompting hepatotoxicity in high doses. Ascorbic acid is another promising candidate, however its use as a hepatoprotective agent is limited by its chemical instability. Therefore, the aim of the study was to overcome their delivery limitations and enhance their hepatoprotective activity by loading into nanoparticles. Key findingsIn the present study, upon incorporating nicotinamide or ascorbic acid in chitosan nanoparticles, they ameliorated the insulin-resistant status induced in rats by a high-fat-high-fructose (HFHF) diet. Both formulae decreased serum level of ALT and AST, as well as liver tissue total cholesterol, triglycerides and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. They also decreased oxidative and nitrosative stresses along with a significant increase in the hepatocellular energy. The biochemical findings were further confirmed by histopathological examination. Finally from the obtained data it could be concluded that chitosan nicotinamide nanoparticles at a dose level (10 mg/kg, p.o.) demonstrated beneficial pharmacological effect with safer toxicity profile than chitosan ascorbic acid nanoparticles. SignificanceNicotinamide chitosan nanoparticles could be recommended as daily supplement in the recovery from NAFLD.

Effects of Dietary Brown Rice on Carcass Composition and Nitric Oxide (NOx) Metabolite Levels in High-Fat High-Fructose Diet-induced Sprague Dawley Rats as Obesity Model

Obesity is characterized by excessive accumulation of fat in the body, which causes changes in body composition and endothelial dysfunction due to impaired production of nitric oxide (NO). The common means of managing obesity is through functional food, such as brown rice, which has high fiber and antioxidant content. Therefore, the purpose of this study was to determine the effect of adding brown rice to feed on carcass composition and NOx levels in obese rats. This was an experimental study involving male Sprague Dawley rats placed in 5 groups, in which 4 were allowed to turn to obese rats with the remaining one group as control. These 4 groups were allowed to later feed on high-fat high-fructose (HFHF) diet while the control fed on the normal AIN-93 diet, followed by 8 weeks of HFHF intervention and brown rice in feed with 3 different doses; 12.43%; 24.86%; and 37.29%. The serum NOx levels were analyzed by the Griess Reaction method, while the percentage of protein and fat was analyzed through Gravimetric Extraction. The results showed that the addition of brown rice resulted in changes in the Lee index (p = 0.000) and abdominal circumference (p = 0.000). Also, a correlation was observed between the Lee index and abdominal circumference (p = 0.001; r = 0.558) of rats. However, there was no significant difference between NOx and carcass protein levels, and there was an increase in carcass fat levels due to an increase in mitochondrial energy efficiency and resistance to protein synthesis in obese rats.

Sea cucumbers-derived sterol sulfate alleviates insulin resistance and inflammation in high-fat-high-fructose diet-induced obese mice

Sea cucumbers are widely consumed in traditional medicine and food. Sea cucumbers-derived sulfated sterol exhibits a sulfate group at C-3 position, which is different from phytosterol with a hydroxyl group. However, the effect of sterol sulfate on metabolic syndrome remains unknown. The purpose of the present study is to investigate the alleviation of sterol sulfate on high-fat-high-fructose diet (HFFD)-induced insulin resistance and inflammation. After 2 weeks feeding with HFFD, male C57BL/6J mice were continuously fed with HFFD plus 0.4 % (w/w) sterol sulfate or phytosterol for 6 weeks. The OGTT was carried out at 7 weeks. At the end of the experimental period, the changes of glycogen, circulating glucose, insulin, pro-inflammatory cytokine and adiponectin were measured. H&E staining was used to observe the morphological changes in adipose tissue. Furthermore, the underlying molecular mechanisms were investigated. Dietary sterol sulfate was superior to phytosterol in reducing body weight gain, adipocyte hypertrophy, and levels of circulating glucose and insulin, as well as increasing the glycogen content of tissues. Furthermore, sterol sulfate ameliorated insulin resistance mainly due to the inhibition of gluconeogenesis, the promotion of glycogen synthesis and GLUT4 translocation by activating PI3K/Akt signaling pathway. Additionally, sterol sulfate effectively attenuated inflammation by increasing serum adiponectin and reducing pro-inflammatory cytokine release. Sterol sulfate exhibited a more significant effect than phytosterol in alleviating HFFD -induced insulin resistance and inflammation, which might be closely related to the sulfate group. The results might provide insights into the prevention and alleviation of metabolic syndrome.

Tibolone regulates systemic metabolism and the expression of sex hormone receptors in the central nervous system of ovariectomised rats fed with high-fat and high-fructose diet

Estrogen replacement therapy decreases some risk factors of the metabolic syndrome but increases the risk of some types of cancer. Tibolone (TIB) has shown similar neuroprotective effects as estrogens. This study aimed to evaluate the effects of TIB on metabolic parameters and the expression of sex hormone receptors in the CNS in ovariectomised rats fed with a hypercaloric diet.Sprague-Dawley female rats were ovariectomised and fed for 30 days with a standard diet (SD) or high-fat high-fructose diet (HFFD) and treated with TIB (1 mg/kg) or vehicle. At the end of the treatments, HFFD increased body weight, glucose tolerance, triglycerides and cholesterol levels, while TIB treatment decreased these parameters.Subsequently, the hippocampus, the hypothalamus and the frontal cortex were dissected. RT-PCR was performed for progesterone receptor (PR), androgen receptor (AR), estrogen receptors alpha and beta (ERα, ERβ), insulin receptor (IR) and insulin-like growth factor 1 (IGF-1). HFFD altered the expression of sex hormone receptors in specific brain structures involved in the regulation of homeostasis and cognition, which highlights the importance of a healthy diet. In turn, TIB modulated the expression of these receptors, particularly in the hypothalamus.

Impact of improving eating habits and rosmarinic acid supplementation on rat vascular and neuronal system in the metabolic syndrome model.

Decreasing high fat and high carbohydrate intake, together with the administration of natural bioactive drugs, is assumed to have a protective effect in the prevention and amelioration of the metabolic syndrome (MetS). The aim of the study was to evaluate effects of diet improvement and/or a phenolic compound (rosmarinic acid; RA) administration (100 mg/kg per d) on metabolic as well as functional changes of vessels and hippocampus caused by the MetS-like conditions. The MetS-like conditions were induced by a high-fat-fructose diet (HFFD) in Prague hereditary hypertriacylglycerolaemic (HTG) rats. The effect of diet improvement and RA administration was studied using biochemical and functional measurements. Consumption of HFFD by HTG rats resulted in the development of conditions like the MetS. The fat and fructose restriction from the diet led to amelioration of basic indicators of metabolic state in rats fed HFFD and to amendment parameters of glucose tolerance test and reduction of the IL-1β serum levels. Moreover, aortic endothelial function was improved with an impact on blood pressure. The functional measurement of electrophysiology of the hippocampus showed that long-term potentiation of neuronal transmission course deteriorated after HFFD was improved by energy restriction. Oral administration of RA had a supporting effect not only on lipid and glucose metabolism but also on the vascular endothelium. Combination of both types of therapy induced beneficial effect on glucose tolerance and lipid peroxidation. Thus, combined improvement of diet habits and treatment with natural bioactive drugs is assumed to have protective effect in prevention and amelioration of the MetS.

Protective effect of fenofibrate against high-fat-high-fructose diet induced non-obese NAFLD in rats.

The present study evaluated the protective effects of fenofibrate on liver function, oxidant-antioxidant balance, and insulin resistance (IR) in rats fed high-fat-high-fructose diet (HFFD). Twenty-four male Sprague-Dawley rats (110-130gm) were allocated into four equal groups (n=6). Rats in group I were fed a normal diet for 4weeks. Rats in group II were fed a normal diet with fenofibrate at 50mg/kg/day orally for four weeks. Rats in group III were fed a normal diet mixed with 25% palm oil and given 60% fructose solution orally for 4weeks. Rats in group IV were fed a normal diet mixed with 25% palm oil, 60% oral fructose solution, and fenofibrate at 50mg/kg/day orally for four weeks. After experimental induction, serum and liver tissue samples were collected to determine lipid profiles, glycemic status, antioxidant status, oxidative and stress markers, and histopathology of liver tissues. The results of the present study revealed that fenofibrate prevents the occurrence of fatty liver, enhancing glycemic status, decreasing oxidative stress, and improving antioxidant status. It can be concluded that fenofibrate has a lipotropic and antidiabetic role.

Apoptosis-inducing factor deficient mice fail to develop hepatic steatosis under high fat high fructose diet or bile duct ligation.

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein involved in redox signalling and programmed cell death. The role of AIF has been well recognized in diabetes and obesity. However, the aspect of AIF deficiency in the development of hepatic steatosis and liver injury is unknown. Therefore, in the current study, Harlequin (Hq mutant) mouse with markedly reduced content of AIF was investigated to explore the role of AIF on the initiation of liver injury. The wild type (WT) developed physiological and pathological features of non-alcoholic fatty liver disease (NAFLD) that were not seen in the Hq mice with AIF deficiency, when fed on high fat high fructose (HFHF) diet. Following bile duct ligation (BDL), the liver associated pathological changes were less conspicuous in Hq mice as compared to WT mice. The expression of AIF protein and apoptosis was markedly lesser as compared to their respective control in Hq mice on HFHF diet. Furthermore, the genes involved in fatty acid metabolism were also altered in the group of treated Hq mice. In conclusion, Hq mice failed to develop diet induced hepatic steatosis, suggestive of a role of AIF mediated pathway in the initiation and progression of liver inflammation. Thus, partial loss of AIF appears to be hepatoprotective. SIGNIFICANCE OF THE STUDY: AIF deficiency has multiple roles in altered pathology processes and cellular metabolism, thereby compromising the cellular homeostasis. Considering the molecular functions of AIF in other organ pathology little is known about its role in diet induced liver injury. Hence, the aim of the current study was to investigate the role of AIF deficiency in liver injury and diseases with focus on NAFLD. The study will help to deliniate the mechanisms of NAFLD using Harliquin Mice.

Fortified vegetarian milk for prevention of metabolic syndrome in rats: impact on hepatic and vascular complications

Metabolic syndrome (MetS) is characterized as a gathering of various metabolic disorders, for example, hyperglycemia, dyslipidemia, and obesity. The present research was conducted to prepare fortified almond milk as functional beverages and evaluate their protective effect against MetS and associated hepatic and vascular complications. Three beverages (I, II, and III) were prepared by fortification almond milk with carrot juice or powder of quinoa seeds and carrot juice or oat powder and banana juice. The sensory attributes, physicochemical properties, bioactive compounds (total phenolic, beta-carotene, tocopherols) and B-complex vitamins were determined in the beverages. In-vitro antioxidant activity of the beverages was assessed. MetS was induced in rats via feeding on high-fat high-fructose diet (HFHF). The biochemical (lipid profile, oxidative stress, liver, and kidney functions), nutritional and histopathological parameters were assessed in rats. The beverage I recorded the highest sensory attributes' scores. The physicochemical properties of the beverages revealed that acidity and viscosity of all beverages ranged from 4.55 to 4.88 and from 40 to 59, respectively. The beverage I showed the highest content of alpha-tocopherol (14.994 μg/g) and beta-carotene (104.541 μg/g), while the beverage II showed the highest content of gamma-tocopherol (0.557 μg/g), folic acid (0.806 μg/g), and total phenols (147.43 μg GAE/g). The results of animals revealed that the beverage II was the most promising in attenuation levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, malondialdehyde, and tumor necrosis factor-alpha. Also, the beverage II was the superior in the protection of the liver and heart tissues as reflected by the histopathological examination findings. So, it can be concluded that the newly prepared almond milk with quinoa seeds and carrot juice could be used as an effective functional beverage for the prevention of MetS and its complications.

Adoptive Cell Transfer of Regulatory T Cells Exacerbates Hepatic Steatosis in High-Fat High-Fructose Diet-Fed Mice

Background and Aims: Non-alcoholic steatohepatitis (NASH) is a multisystem condition, involving the liver, adipose tissue, and immune system. Regulatory T (Treg) cells are a subset of T cells that exert an immune-controlling effect. Previously, a reduction of Treg cells in the visceral adipose tissue (VAT) was shown to be associated with a more severe degree of liver disease. We aimed to correct this immune disruption through adoptive cell transfer (ACT) of Treg cells.Methods: Male 8-week-old C57BL/6J mice were fed a high-fat high-fructose diet (HFHFD) for 20 weeks. Treg cells were isolated from the spleens of healthy 8 to 10-week-old C57BL/6J mice and were adoptively transferred to HFHFD-fed mice. PBS-injected mice served as controls. Plasma ALT and lipid levels were determined. Liver and adipose tissue were assessed histologically. Cytotoxic T (Tc), Treg, T helper (Th) 1 and Th17 cells were characterized in VAT, liver, subcutaneous adipose tissue (SAT), blood, and spleen via flow cytometry. Gene expression analysis was performed in SAT and VAT of mice fed either the HFHFD or a control diet for 10–32 weeks.Results: ACT increased Treg cells in SAT, but not in any of the other tissues. Moreover, the ACT induced a decrease in Th1 cells in SAT, liver, blood, and spleen. Higher plasma ALT levels and a higher degree of steatosis were observed in ACT mice, whereas the other HFHFD-induced metabolic and histologic disruptions were unaffected. Expression analysis of genes related to Treg-cell proliferation revealed a HFHFD-induced decrease in all investigated genes in the SAT, while in the VAT the expression of these genes was largely unaffected, except for a decrease in Pparg.Conclusion: ACT of Treg cells in HFHFD-fed mice exacerbated hepatic steatosis, which was possibly related to the increase of Treg cells in the SAT and/or the general decrease in Th1 cells. Moreover, the HFHFD-induced decrease in Pparg expression appeared critical in the decrease of Treg cells at the level of the VAT and the inability to replenish the amount of Treg cells by the ACT, while the mechanism of Treg cell accumulation at the level of the SAT remained unclear.

Anti-inflammatory and anti-oxidant effects of aloe vera in rats with non-alcoholic steatohepatitis.

BACKGROUNDAloe vera exerts several biological activities, such as, anti-inflammatory, antioxidant, and antimicrobial effects. It was recently shown to reduce insulin resistance and triglyceride level. We hypothesized that aloe vera would have beneficial effects in alleviating non-alcoholic steatohepatitis (NASH) in rats.AIMTo examine the therapeutic effects of aloe vera in NASH rats.METHODSAll rats were randomly divided into 3 groups (n = 6 in each group). Rats in the control group were fed ad libitum with a standard diet for 8 wk. Rats in the NASH group were fed ad libitum with a high-fat high-fructose diet (HFHFD) for 8 wk. Rats in the aloe vera group were fed ad libitum with a HFHFD and aloe vera in dimethylsulfoxide (50 mg/kg) by gavage daily for 8 wk. Liver samples were collected at the end of the treatment period.RESULTSHepatic malondialdehyde (MDA) levels increased significantly in the NASH group as compared with the control group (377 ± 77 nmol/mg vs 129 ± 51 nmol/mg protein, respectively, P < 0.001). Glutathione (GSH) levels were significantly lower in the NASH group than the control group (9 ± 2 nmol/mg vs 24 ± 8 nmol/mg protein, respectively, P = 0.001). The expression of interleukin-18 (IL-18), nuclear factor-kappa β, and caspase-3 increased, while peroxisome proliferator-activated receptor gamma decreased in the NASH group compared with the controls. Following aloe vera administration, MDA levels decreased (199 ± 35 nmol/mg protein) and GSH increased (18 ± 4 nmol/mg protein) markedly. Steatosis, hepatocyte ballooning, lobular inflammation and increased hepatocyte apoptosis were observed in the NASH group. Aloe vera treatment attenuated these changes in liver histology.CONCLUSIONAloe vera attenuated oxidative stress, hepatic inflammation and hepatocyte apoptosis, thus improving liver pathology in rats with NASH.

Melatonin regulates neurodegenerative complications associated with NAFLD via enhanced neurotransmission and cellular integrity: a correlational study.

Nonalcoholic fatty liver disease (NAFLD) is recognized globally as the leading cause of chronic liver diseases whose patients are asymptomatic and are diagnosed incidentally. It increases the rate of mortality which is usually related to cardiovascular events; however, scarce attention has been addressed to brain damage. This study was designed to investigate the impact of melatonin (MEL; 10mg/kg) on overcoming the hepato and neuro-complications associated with high fat, high fructose (HFHF) diet induced-NAFLD in rats. NAFLD was induced by HFHF diet for 8 consecutive weeks. MEL was given orally for the last 10days. Rats' general behavior was assessed by; open field test (OFT) and forced swimming test (FST). On biochemical level; serum levels of glucose, insulin, alanine transaminase and aspartate transaminase as well as the hepatic levels of triglycerides and total cholesterol were evaluated. Monoamines' brain levels, their metabolites in addition to the brain level of 8-hydroxyguanosine (8-OHdG) were evaluated. Moreover, the levels of tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (NOx) were measured in both the liver and brain tissues. Oral treatment of NAFLD induced rats with MEL for ten consecutive days managed to increase the activity of the rats in the OFT and decrease the immobility period in the FST. Moreover, MEL reduced monoamines turnover and elevated brain 8-OHdG level. It also had the ability to counteract the elevated levels of GSH, NOx, MDA, and TNF- α in liver and brain tissues. MEL can be suggested to be a promising candidate for treating the neuronal side effects related to NAFLD.

Pathobiological and molecular connections involved in the high fructose and high fat diet induced diabetes associated nonalcoholic fatty liver disease.

Poor dietary habits such as an over consumption of high fructose and high fat diet are considered as the major culprit for the induction of diabetes associated liver injury. Diabetes mellitus is a metabolic disorder that affects various vital organs of the body especially the kidney, brain, heart, and liver. The high fructose and high fat (HFHF) diet worsen the metabolic conditions by producing various pathogenic burdens such as oxidative stress, inflammation, etc. on liver. The hyperlipidemic and hyperglycemic conditions induced by HFHF diet leads to the generation of various proinflammatory mediators like TNFα, interleukin and cytokines. The systematic bibliographicalliterature surveywas done with the help of PubMed, Google scholar and MedLine to identify all pathological and molecularconcerened with HFHF induced diabetic liver injury. Theconsumption of HFHF diet leads to an increase in mitochondrial oxidative stress thereby decreases the liver protective antioxidants required for cell viability. HFHF diet disturbs lipid and lipoprotein clearance by elevating the level of apolipoprotein CIII and impairing the hydrolysis of triglyceride. As a result, there is an increase in free fatty acid concentration, triglycerides and diacylglycerol in the liver which further triggers the situation of insulin resistance. The focus of present review is based upon the various pathological, genetic and molecular mechanism involved in the development of high-fat high fructose diet induced diabetic liver injury. However, the current review also documented few shreds of evidence related to various microRNAs (miR-31, miR-33a, miR-34a, miR-144, miR-146b, miR-150) concerned to HFHF diet which play an important role in the pathogenesis of diabetes associated liver injury Dietary life style modification may prove beneficial in the management of various metabolic disorders.

Mitigation of renal inflammation and endoplasmic reticulum stress by vildagliptin and statins in high-fat high-fructose diet-induced insulin resistance and renal injury in rats

Dyslipidemia and insulin resistance in obesity can lead to lipotoxicity and cellular damage. Renal lipotoxicity in association with an impairment of lipid metabolism induces renal damage through the activation of inflammation, ER stress, fibrosis and apoptosis. We investigated the effects of a combination treatment of the DPP-4 inhibitor vildagliptin and atorvastatin on renal lipotoxicity related to renal dysfunction and injury in a high-fat high-fructose diet (HFF)-induced insulin resistant condition. Male Wistar rats were fed on a high-fat diet and were given drinking water with 10% fructose for 16 weeks. After that, rats were divided into: no treatment (HFF), treatment with vildagliptin, atorvastatin and vildagliptin plus atorvastatin for 4 weeks. The results demonstrated that the combination treatment prominently improved insulin resistance, dyslipidemia and kidney morphological changes induced by HFF. These changes correlated well with the increased expression of nephrin and podocin and decreased urine protein. Notably, the combined treatment produced greater improvement in renal lipid metabolism through increasing fatty acid oxidation with the decreases in fatty acid transporters and fatty acid synthesis, thereby reducing renal lipid accumulation in HFF rats. The reduction in renal lipotoxicity via diminishing renal inflammation, ER stress, fibrosis and apoptosis was also more significant in the combined treatment group than in the other groups in which the drug was used as a monotherapy. In conclusion, the combination therapy produced synergistic beneficial effects on metabolic parameters, lipid metabolism and accumulation related to renal lipid accumulation-induced lipotoxicity and kidney injury in the HFF-induced insulin resistant model with improved outcomes.

Substitution of high-dose sucrose with fructose in high-fat diets resulted in higher plasma concentrations of aspartic acid, cystine, glutamic acid, ornithine and phenylalanine, and higher urine concentrations of arginine and citrulline

High fructose intake has been shown to increase circulating alanine transaminase in humans, which could reflect damage to the liver by fructose but could also be linked to higher level of transamination of amino acids in liver. Therefore, we hypothesized that a diet with high content of fructose would affect the amino acid composition in rat plasma and urine differently from a diet with high sucrose content. Because high intake of sucrose and fructose is often accompanied with high intake of saturated fat in the Western-style diet, we wanted to compare the effects of high fructose/sucrose in diets with normal or high content of coconut oil on individual free amino acids plasma and urine. Male Wistar rats were fed diets with normal (10 wt%) or high (40 wt%) content of sucrose or fructose, with normal or high fat content (7 or 22 wt%) and 20 wt% protein (casein). Rats fed high-fructose high-fat diet had higher plasma concentrations of aspartic acid, cystine, glutamic acid, ornithine, and phenylalanine and higher urine concentrations of arginine and citrulline when compared to rats fed high-sucrose high-fat diet. Substituting normal content of sucrose with fructose in the diets had little impact on amino acids in plasma and urine. Serum concentrations of alanine transaminase, aspartate transaminase, and creatinine, and urine cystatin C and T cell immunoglobulin mucin-1 concentrations were comparable between the groups and within normal ranges. To conclude, substituting high-dose sucrose with high-dose fructose in high-fat diets affected amino acid compositions in plasma and urine.

1824-P: Activation of Cardiac Mitochondrial Akt1 Improved Diabetic Cardiomyopathy through Inhibition of Melatonin Degradation and Remotely Improved Liver Metabolism

Insulin resistance impaired Akt1 translocation to mitochondria in myocardium and contributed to diabetic cardiomyopathy (DCM). It is unknown whether activation of mitochondrial Akt in cardiac muscle can protect against DCM. To this end, we generated an inducible heart-specific transgenic mice with a mitochondria-targeting constitutively active Akt (CAMCAKT). A high fat-high fructose (HFF) diet induced myocardial fibrosis and heart failure, but cardiomyopathy was reversed in the CAMCAKT mice, indicating a mechanistic role of mitochondrial Akt1 signaling in DCM. RNAseq analysis revealed myocardial transcriptome changes, including suppressed Col1a1 and Col3a1 expression (fibrosis markers) recapitulating the mechanism of fibrosis. Accompanying lowered GP6 expression suggested a reduction in collagen-induced platelet activation. Pathway analysis revealed significant inhibition in multiple steps of melatonin degradation. Enhancing melatonin signaling, an emerging myocardial protective factor that reduces oxidative stress/apoptosis, is a novel mechanism through which mitochondrial Akt1 could protect against DCM. Under the HFF diet, cardiac mitochondrial Akt1 signaling also caused whole body changes; CAMCAKT mice had 15% less body fat, 30% lower total cholesterol and 42% lower LDL (p&amp;lt;0.05), and showed higher energy expenditure during night cycles and an elevated RER, an indicator for increased carbohydrate metabolism. The diet-induced fatty liver in the CAMCAKT mice was significantly lowered, suggesting that cardiac mitochondrial Akt signaling could remotely modulate hepatic fat metabolism. Liver RNAseq revealed that cholesterol synthesis in the liver was modulated by cardiac mitochondria. In summary, activating cardiac mitochondrial Akt1 protected against DCM by inhibiting melatonin degradation, and attenuated the development of fatty liver by regulating cholesterol synthesis. Disclosure A. Ta: None. Y. Chen: None. Y. Chen: None. H.Y.H. Lin: None. P.H. Wang: Board Member; Self; Dianavi. Funding National Institutes of Health (R01HL096987)

Effect of Oral Administration of Weissella confusa on Fecal and Plasma Ethanol Concentrations, Lipids and Glucose Metabolism in Wistar Rats Fed High Fructose and Fat Diet.

Background and PurposeIn previous investigations, Weissella confusa was shown to lack the metabolic pathway from fructose to mannitol and to produce ethanol when cultivated in the presence of fructose. Hence, we assessed the effect of oral administration of W. confusa (strain NRRL-B-14171) on blood and fecal ethanol concentrations, glucose and lipid metabolism and traits of the metabolic syndrome in Wistar rats (n=27) fed diets with two different fat and fructose levels and with or without the addition of W. confusa during a total intervention time of 15 weeks (105 days).Materials and MethodsFrom week 1 to 6, rats were given a medium fructose and fat (MFru-MF) diet containing 28% fructose and 10% fat without the addition of W. confusa (control group, n=13) or mixed with 30 g per kg diet of lyophilized W. confusa (10.56 ± 0.20 log CFU/g; W. confusa group, n=14). From week 7 to 15, the percentage of dietary fructose and fat in the control and W. confusa group was increased to 56% and 16%, respectively (high fructose-high fat (HFru-HF) diet).ResultsIn HFru-HF-fed rats, W. confusa was detected in feces, regardless of whether W. confusa was added to the diet or not, but not in rats receiving the MFru-MF diet without added W. confusa or in an additional control group (n=10) fed standard rat food without fructose, increased fat content and W. confusa. This indicates that fecal W. confusa may be derived from orally administered W. confusa as well as – in the case of high fructose and fat intake and obesity of rats – from the intestinal microbiota. As shown by multifactorial ANOVA, blood ethanol, the relative liver weight, serum triglycerides, and serum cholesterol as well as fecal ethanol, ADH, acetate, propionate and butyrate, but not lactate, were significantly higher in the W. confusa – compared to the control group.DiscussionThis is the first in vivo trial demonstrating that heterofermentative lactic acid bacteria lacking the mannitol pathway (like W. confusa) can increase fecal and blood ethanol concentrations in mammals on a high fructose-high fat diet. This may explain why W. confusa resulted in hyperlipidemia and may promote development of NAFLD in the host.

Perindopril ameliorates experimental Alzheimer's disease progression: role of amyloid β degradation, central estrogen receptor and hyperlipidemic-lipid raft signaling.

Accumulating evidence indicates that over-stimulation of angiotensin-converting enzyme 1 (ACE1) activity is associated with β-amyloid (Aβ) and phosphorylated tau (p-tau)-induced apoptosis, oxido-nitrosative neuroinflammatory stress and neurodegeneration in Alzheimer's disease (AD). Alternatively, activation of the ACE2, the metalloprotease neprilysin (Neutral Endopeptidase; NEP) and the insulin-degrading enzyme (IDE) could oppose the effects of ACE1 activation. We aim to investigate the relationship between ACE1/ACE2/NEP/IDE and amyloidogenic/hyperlipidemic-lipid raft signaling in hyperlipidemic AD model. Induction of AD was performed in ovariectomized female rats with high-fat high fructose diet (HFFD) feeding after 4weeks following D-galactose injection (150mg/kg). The brain-penetrating ACE1 inhibitor perindopril (0.5mg/kg/day, p.o.) was administered on a daily basis for 30days. Perindopril significantly decreased hippocampal expression of ACE1 and increased expression of ACE2, NEP and IDE. Perindopril markedly decreased Aβ1-42, improved lipid profile and ameliorated the lipid raft protein markers caveolin1 (CAV1) and flotillin 1 (FLOT1). This was accompanied by decreased expression of p-tau and enhancement of cholinergic neurotransmission, coupled with decreased oxido-nitrosative neuroinflammatory stress, enhancement of blood-brain barrier (BBB) functioning and lower expression of the apoptotic markers glial fibrillary acidic protein (GFAP), Bax and β-tubulin. In addition, perindopril ameliorated histopathological damage and improved learning, cognitive and recognition impairment as well as depressive behavior in Morris water maze, Y maze, novel object recognition and forced swimming tests, respectively. Conclusively, perindopril could improve cognitive defects in AD rats, at least through activation of ACE2/NEP/IDE and inhibition of ACE1 and subsequent modulation of amyloidogenic/hyperlipidemic-lipid raft signaling and oxido-nitrosative stress.