Betaine supplementation prevents fatty liver induced by a high-fat diet: effects on one-carbon metabolism

The purpose of this study was to examine the effects of betaine supplementation on the regulation of one-carbon metabolism and liver lipid accumulation induced by a high-fat diet in rats. Rats were fed one of three different liquid diets: control diet, high-fat diet and high-fat diet supplemented with betaine. The control and high-fat liquid diets contained, respectively, 35 and 71 % of energy derived from fat. Betaine supplementation involved the addition of 1 % (g/L) to the diet. After three weeks on the high-fat diet the rats had increased total liver fat concentration, liver triglycerides, liver TBARS and plasma TNF-α. The high-fat diet decreased the hepatic S-adenosylmethionine concentration and the S-adenosylmethionine/S-adenosylhomocysteine ratio compared to the control as well as altering the expression of genes involved in one-carbon metabolism. Betaine supplementation substantially increased the hepatic S-adenosylmethionine concentration (~fourfold) and prevented fatty liver and hepatic injury induced by the high-fat diet. It was accompanied by the normalization of the gene expression of BHMT, GNMT and MGAT, which code for key enzymes of one-carbon metabolism related to liver fat accumulation. In conclusion, the regulation of the expression of MGAT by betaine supplementation provides an additional and novel mechanism by which betaine supplementation regulates lipid metabolism and prevents accumulation of fat in the liver.     

Rosiglitazone and fenofibrate improve insulin sensitivity of pre-diabetic OLETF rats by reducing malonyl-CoA levels in the liver and skeletal muscle

AimsRosiglitazone and fenofibrate, specific agonists of the peroxisome proliferator activated receptors-γ (PPARγ) and -α (PPARα), respectively, improve insulin sensitivity in diabetic animals and in patients with type 2 diabetes. Here we investigated how pre-diabetic Otsuka Long–Evans Tokushima Fatty (OLETF) rats fed with normal and high-fat diets respond to these PPAR agonists.Main methodsPre-diabetic OLETF rats were subjected to high-fat or standard diets with or without rosiglitazone or fenofibrate for 2 weeks. The metabolism of the rats and the levels of malonyl-CoA and activities of malonyl-CoA decarboxylase (MCD), acetyl-CoA carboxylase (ACC), and AMP-activated protein kinase (AMPK) in metabolic tissues were assessed.Key findingsRosiglitazone and fenofibrate significantly improved insulin sensitivity and reduced the levels of plasma triglycerides and free fatty acids in OLETF rats fed with a high-fat diet. Fenofibrate particularly reduced the body weight, fat, and total cholesterol in high fat diet OLETF rats. The highly elevated malonyl-CoA levels in the skeletal muscle and liver of OLETF rat were significantly reduced by rosiglitazone or fenofibrate due to, in part, the increased MCD activities and expression. On the other hand, ACC activities were unchanged in skeletal muscle and decreased in liver in high fat diet group. AMPK activities were dramatically decreased in OLETF rats and not affected by these agonists.SignificanceThese results demonstrate that treatment of pre-diabetic OLETF rats–particularly those fed a high-fat diet–with rosiglitazone and fenofibrate significantly improves insulin sensitivity and fatty acid metabolism by increasing the activity of MCD and reducing malonyl-CoA levels in the liver and skeletal muscle.     

Effects of supplementing different chromium histidinate complexes on glucose and lipid metabolism and related protein expressions in rats fed a high-fat diet

BackgroundThe objective of this study was to investigate the effects of different chromium histidinate (CrHis) complexes added to the diet of rats fed a high-fat diet (HFD) on body weight changes, glucose and lipid metabolism parameters, and changes in biomarkers such as PPAR-γ, IRS-1, GLUTs, and NF-κB proteins.MethodsForty-two Sprague–Dawley rats were divided equally into six groups and fed either a control, an HFD, or an HFD supplemented with either CrHis1, CrHis2, CrHis3, or a combination of the CrHis complexes as CrHisM.ResultsFeeding an HFD to rats increased body weights, HOMA-IR values, fasting serum glucose, insulin, leptin, free fatty acid, total cholesterol, low-density lipoprotein cholesterol, and MDA concentrations as well as AST activities, and decreased serum and brain serotonin concentrations compared with rats fed a control diet (P < 0.0001). The levels of the PPAR-γ, IRS-1, and GLUTs in the liver and brain decreased, while NF-κB level increased, with feeding an HFD (P < 0.05). Although all the CrHis supplements reversed the negative effects of feeding an HFD (P < 0.05), the CrHis1 complex was most effective in changing the protein levels, while CrHisM was most effective in influencing certain parameters such as body weight and serum metabolites.ConclusionThe results of the present work suggest that the CrHis1 complex is most potent for alleviating the negative effects of feeding an HFD. The efficacy of CrHisM is likely due to the presence of the CrHis1 complex.     

Chitosan reduces inflammation and protects against oxidative stress in a hyperlipidemic rat model: relevance to nonalcoholic fatty liver disease

Background

An altered lipid profile may lead to the development of inflammation and NAFLD (Non-alcoholic fatty liver disease). Although statins have a positive effect on blood lipid levels their long-term use is known to cause adverse effects, in this backdrop there is an interest in natural compounds which may affect lipid metabolism and prevent NAFLD. We have examined the effect of Chitosan on rats subjected to a high-fat diet.

Methods and results

Male Wistar middle aged rats (12–16 months) were treated with high-fat diet orally for two months for creating a NAFLD model. Rats were also supplemented with Chitosan (2% chitosan daily) for 2 months. We assessed the activity of antioxidant enzymes, the histopathological profile of the liver. Inflammatory cytokines and adiponectin levels were also measured in serum. HFD induced significant changes in liver tissue and inflammatory markers (Il-6, TNF- alpha, NF-KB). Chitosan treatment protected rats from HFD induced alterations.

Conclusions

The findings suggest that Chitosan can effectively improve liver lipid metabolism by normalizing cholesterol, triglyceride, lowering NF-KB expression, and protecting the liver from oxidative stress by improving hepatic function. Chitosan also regulates genes related to lipidemic stress i,e leptin and adiponectin.

     

Lack of Cyclin E1 in hepatocytes aggravates ethanol-induced liver injury and hepatic steatosis in experimental murine model of acute and chronic alcohol-associated liver disease

BackgroundCyclin E1 is the regulatory subunit of cyclin-dependent kinase 2 (Cdk2) and one of the central players in cell cycle progression. We recently showed its crucial role for initiation of liver fibrosis and hepatocarcinogenesis. In the present study, we investigated the role of Cyclin E1 in the development of alcohol-associated liver disease (ALD).MethodsMice with constitutive (E1^?/?), hepatocyte-specific (Cyclin E1^Δhepa), or intestinal-epithelial-cell-specific (Cyclin E1^ΔIEC) inactivation of Cyclin E1 and corresponding wild type littermate controls (WT) were administered either a Lieber-DeCarli ethanol diet (LDE) for 3 weeks or acute ethanol binges (6 g/kg) through oral gavage. Serum parameters of liver functionality were measured; hepatic tissues were collected for biochemical and histological analyses.ResultsThe administration of acute EtOH binge and chronic LDE diet to E1^?/? mice enhanced hepatic steatosis, worsened liver damage and triggered body weight loss. Similarly, in the acute EtOH binge model, Cyclin E1^Δhepa mice revealed a significantly worsened liver phenotype. In contrast, inactivation of Cyclin E1 only in intestinal epithelial cell (IECs)did not lead to any significant changes in comparison to WT mice after acute EtOH challenge. Remarkably, both acute and chronic EtOH administration in E1^?/? animals resulted in increased levels of ADH and decreased expression of ALDH1/2. The additional application of a pan-Cdk inhibitor (S-CR8) further promoted liver damage in EtOH-treated WT mice.ConclusionOur data point to a novel unexpected role of Cyclin E1 in hepatocytes for alcohol metabolism, which seems to be independent of the canonical Cyclin E1/Cdk2 function as a cell cycle regulator.     

Nonalcoholic fatty liver disease impairs the cytochrome P-450-dependent metabolism of α-tocopherol (vitamin E)

This study aims to investigate in in vivo and in vitro models of nonalcoholic fatty liver disease (NAFLD) the enzymatic metabolism of α-tocopherol (vitamin E) and its relationship to vitamin E-responsive genes with key role in the lipid metabolism and detoxification of the liver. The experimental models included mice fed a high-fat diet combined or not with fructose (HFD+F) and HepG2 human hepatocarcinoma cells treated with the lipogenic agents palmitate, oleate or fructose. CYP4F2 protein, a cytochrome P-450 isoform with proposed α-tocopherol ω-hydroxylase activity, decreased in HFD and even more in HFD+F mice liver; this finding was associated with increased hepatic levels of α-tocopherol and decreased formation of the corresponding long-chain metabolites α-13-hydroxy and α-13-carboxy chromanols. A decreased expression was also observed for PPAR-γ and SREBP-1 proteins, two vitamin E-responsive genes with key role in lipid metabolism and CYP4F2 gene regulation. A transient activation of CYP4F2 gene followed by a repression response was observed in HepG2 cells during the exposure to increasing levels of the lipogenic and cytotoxic agent palmitic acid; such gene repression effect was further exacerbated by the co-treatment with oleic acid and α-tocopherol and was also observed for PPAR-γ and the SREBP isoforms 1 and 2. Such gene response was associated with increased uptake and ω-hydroxylation of α-tocopherol, which suggests a minor role of CYP4F2 in the enzymatic metabolism of vitamin E in HepG2 cells. In conclusion, the liver metabolism and gene response of α-tocopherol are impaired in experimental NAFLD.     

Modulation of hepatic lipidome by rhodioloside in high-fat diet fed apolipoprotein E knockout mice

BackgroundRhodioloside is a glucoside of tyrosol isolated from Rhodiola rosea. However, its regulating effect on hepatic dyslipidemia of atherogenic mice has rarely been studied.PurposeThe specific aims of current study included to clarify lipidomic perturbation in liver tissues of apolipoprotein E deficient (apoE^−/−) mice fed with high-fat diet, and to examine the effects of rhodioloside against atherosclerosis and dyslipidemia.Study DesignThe comparisons of hepatic lipidome were executed between wide type (WT) mice fed with normal diet (NDC) and apoE^−/− mice fed with high-fat diet (Model), WT mice fed with high-fat diet (HFDC) versus the model mice, as well as the model mice versus rhodioloside-treated atherosclerotic mice.MethodsUltra high performance liquid chromatography coupled with a Q exactive hybrid quadrupole-orbitrap mass spectrometry (UPLC-MS/MS) was employed to provide an unbiased and simultaneous measurement of individual lipid species in liver tissues.ResultsMultivariate statistical analysis derived from LC-MS spectra revealed that high-fat diet and apoE deficiency caused a series of disturbances on glyerolipid metabolism, glycerophospholipid metabolism and sphingolipid metabolism. Rhodioloside administration showed atheroprotective effects on the apoE^−/− mice with regulating the levels of 1 phosphatidylcholine, 2 phosphatidylserines, 5 alkyldiacylglycerols and 3 alkenyldiacylglycerols back to normal. In particular, PC (4:0/15:0) was positively associated with high-density lipoprotein cholesterol in blood, both of which could be ameliorated by rhodioloside.ConclusionOur results identified the abnormal hepatic lipids in atherosclerosis progression that could efficiently improved by rhodioloside. These lipids contributed to biological understanding of atherogenic dyslipidemia in liver and could also served as sensitive indicators for drug target screening.     

Dietary creatine supplementation lowers hepatic triacylglycerol by increasing lipoprotein secretion in rats fed high-fat diet

Recent studies have shown that dietary creatine supplementation can prevent lipid accumulation in the liver. Creatine is a small molecule that plays a large role in energy metabolism, but since the enzyme creatine kinase is not present in the liver, the classical role in energy metabolism does not hold in this tissue. Fat accumulation in the liver can lead to the development of nonalcoholic fatty liver disease (NAFLD), a progressive disease that is prevalent in humans. We have previously reported that creatine can directly influence lipid metabolism in cell culture to promote lipid secretion and oxidation. Our goal in the current study was to determine whether similar mechanisms that occur in cell culture were present in vivo. We also sought to determine whether dietary creatine supplementation could be effective in reversing steatosis. Sprague–Dawley rats were fed a high-fat diet or a high-fat diet supplemented with creatine for 5 weeks. We found that rats supplemented with creatine had significantly improved rates of lipoprotein secretion and alterations in mitochondrial function that were consistent with greater oxidative capacity. We also find that introducing creatine into a high-fat diet halted hepatic lipid accumulation in rats with fatty liver. Our results support our previous report that liver cells in culture with creatine secrete and oxidize more oleic acid, demonstrating that dietary creatine can effectively change hepatic lipid metabolism by increasing lipoprotein secretion and oxidation in vivo. Our data suggest that creatine might be an effective therapy for NAFLD.     

Postnatal overfeeding promotes early onset and exaggeration of high-fat diet-induced nonalcoholic fatty liver disease through disordered hepatic lipid metabolism in rats

Exposure to overnutrition in critical or sensitive developmental periods may increase the risk of developing obesity and metabolic syndrome in adults. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, but the relationship among postnatal nutrition, lipid metabolism, and NAFLD progression during development remains poorly understood. Here we investigated in a rat model whether postnatal overfeeding increases susceptibility to NAFLD in response to a high-fat diet. Litters from Sprague-Dawley dams were culled to three (small litters) or ten (normal litters) pups and then weaned onto a standard or high-fat diet at postnatal day 21 to generate normal-litter, small-litter, normal-litter/high-fat, and small-litter/high-fat groups. At age 16 weeks, the small-litter and both high-fat groups showed obesity, dyslipidemia, and insulin resistance. Hepatic disorders appeared earlier in the small-litter/high-fat rats with greater liver mass gain and higher hepatic triglycerides and steatosis score versus normal-litter/high-fat rats. Hepatic acetyl-CoA carboxylase activity and mRNA expression were increased in small-litter rats and aggravated in small-litter/high-fat rats but not in normal-litter/high-fat rats. The high expression in small-litter/high-fat rats coincided with high sterol regulatory element-binding protein-1c mRNA and protein expression. However, mRNA expression of enzymes involved in hepatic fatty acid oxidation (carnitine palmitoyltransferase 1) and output (microsomal triglyceride transfer protein) was decreased under a high-fat diet regardless of litter size. In conclusion, overfeeding related to small-litter rearing during lactation contributes to the NAFLD phenotype when combined with a high-fat diet, possibly through up-regulated hepatic lipogenesis.     

The water extract of Sophorae tonkinensis Radix et Rhizoma alleviates non-alcoholic fatty liver disease and its mechanism

BackgroundSophorae tonkinensis Radix et Rhizoma is traditionally used for clearing away heat and toxic materials in China.PurposeThis study aims to observe the amelioration of Sophorae tonkinensis water extract (STR) against non-alcoholic fatty liver disease (NAFLD) and the engaged mechanism.MethodsNAFLD was induced in mice fed by methionine and choline deficient (MCD) diet. Liver histological observation, Oil Red O, Masson's trichrome and F4/80 immunohistochemical staining were performed. Serum and liver biochemical parameters, hepatic gene and protein expression were detected. Cellular lipids accumulation in human normal liver l-02 and hepatoma HepRG cells were induced by 0.5 mM nonestesterified fatty acid (NEFA). The contents of matrine (MT) and oxymatrine (OMT) in STR were detected by using high-performance liquid chromatography (HPLC). Carnitine palmitoyltransferase 1A (CPT1A) expression and enzymatic activity were detected both in vivo and in vitro.ResultsSerum alanine/aspartate aminotransferase (ALT/AST) activity, hepatic malondialdehyde (MDA) content and liver histological observation showed that STR alleviated hepatocellular damage in mice fed with MCD diet. Hepatic triglyceride (TG), total cholesterol (TC) and NEFA amounts, and Oil Red O staining showed that STR reduced hepatic lipids accumulation in mice fed with MCD diet. STR and its main compounds including MT and OMT decreased NEFA-induced cellular lipids accumulation in hepatocytes. STR enhanced CPT1A activity both in vivo and in vitro. MT and OMT also enhanced cellular CPT1A activity in l-02 hepatocytes treated with NEFA. Moreover, the CTP1A inhibitor etomoxir (ETO) reduced the lipid-lowering activity provided by STR, MT or OMT in vitro. Liver myeloperoxidase (MPO) activity and hydroxyproline content, Masson's trichrome and F4/80 immunohistochemical staining, and hepatic mRNA expression of some molecules involved in regulating inflammation or fibrosis demonstrated that STR alleviated hepatic inflammation and liver fibrosis in mice fed with MCD diet.ConclusionSTR alleviated NAFLD by inhibiting hepatic inflammation and liver fibrosis, and reducing hepatic lipids accumulation through promoting fatty acids β-oxidation by enhancing liver CPT1A activity. MT and OMT may be the main active compounds contributing to the lipid-lowering activity provided by STR.     

Altered feeding differentially regulates circadian rhythms and energy metabolism in liver and muscle of rats

Energy metabolism follows a diurnal pattern responding to the light/dark cycle and food availability. This study investigated the impact of restricting feeding to the daylight hours and feeding a high fat diet on circadian clock (bmal1, dbp, tef and e4bp4) and metabolic (pepck, fas, ucp3, pdk4) gene expression and markers of energy metabolism in muscle and liver of rats. The results show that in chow-fed rats switched to daylight feeding, the peak diurnal expression of genes in liver was shifted by 6–12 h while expression of these genes in muscle remained in a similar phase to rats feeding ad libitum. High fat feeding during the daylight hours had limited effect on clock gene expression in liver or muscle but shifted the peak expression of metabolic genes (pepck, fas) in liver by 6–12 h. The differential effects of daylight feeding on gene and protein expression in muscle and liver were accompanied by an 8% reduction in whole body energy expenditure, a 20–30% increased glycogen content during the light phase in muscle of day-fed rats and increased adipose tissue deposition per gram food consumed. These data demonstrate that a mismatch of feeding and light/dark cycle disrupts tissue metabolism in muscle with significant consequences for whole body energy homeostasis.     

The effect of high-fat diet on plasma ghrelin and leptin levels in rats

Ghrelin and leptin regulate appetite and energy homeostasis in humans and rodents. The effects of different nutritional factors on ghrelin and leptin secretion are not well documented in rats. Therefore, the aim of our study was to investigate the effect of a high-fat diet on plasma ghrelin and leptin levels and on adiposity. Twenty male Wistar rats, body weight220–260 g, were used in the study. Rats were randomized either on a standard chow diet (n=10) or on a high-fat diet (a mixture of nuts) forad libitum 11-week period. Body weight was measured once per week. At the end of the nutritional period, rats were sacrificed. Blood was collected for determination of lipids and glucose, as well as plasma ghrelin and leptin levels by ELISA method. The weight of different organs was determined. Rats fed on a high-fat diet showed significant increase in total body weight compared to control group. The long-term intake of high-fat diet caused hyperleptinemia and hypoghrelinemia. There was a significant positive correlation between plasma leptin levels and epididymal fat mass, liver and heart. In contrast, ghrelin levels showed inverse correlation with epididymal fat mass and liver weight. In conclusion, long-term intake of high-fat diet induced changes in plasma ghrelin and leptin in male rats, as well as in epididymal fat mass, liver and heart weights.     

Effect of high-intensity exercise and high-fat diet on lipid metabolism in the liver of rats

[Purpose]

This study investigated the effects of high-intensity exercise (Ex) and high dietary fat intake on lipid metabolism in the liver of rats.

[Methods]

Male Sprague-Dawley rats were randomly assigned to one of the four groups (n=10 per group) that were maintained on a normal diet (ND) or high-fat diet (HFD) consisting of 30% fat (w/w), with or without exercise on a treadmill at 30 m/min and 8% grade) for 4 weeks (i.e., ND, ND+Ex, HFD, and HFD+Ex groups).

[Results]

Body weight (p<.001), total plasma cholesterol (TC) (p<.001), triglyceride (TG) (p<.05), and liver TG levels (p<.05) were increased in the HFD group relative to the ND groups, and serum glucose (p<.05), insulin (p<.05), homeostatic model assessment of insulin resistance (HOMA-IR) (p<.01), and liver TG levels (p<.01) were also higher in the HFD group compared to the ND+Ex group. Plasma free fatty acid was elevated in the HFD+Ex group compared to the HFD group (p<.01). With the exception of acetyl coenzyme A carboxylase, the expression of lipid metabolism-related genes in the liver was altered in the Ex groups compared to the control group (p<.05), with genes involved in lipolysis specifically up regulated in the HFD+Ex group compared to the other groups.

[Conclusion]

Vigorous exercise may increase glucose utilization and fat oxidation by activating genes in the liver that are associated with lipid metabolism compared to that in animals consuming a HFD without exercise. Therefore, high intensity exercise can be considered to counter the adverse effects of high dietary fat intake.     

The effect of the use of copper carbonate and copper nanoparticles in the diet of rats on the level of β-amyloid and acetylcholinesterase in selected organs

BackgroundCopper has an important role in nervous system function, as a cofactor of many enzymes and in the synthesis of neurotransmitters. Both the dose and the chemical form of copper can determine the impact of this element on metabolism, the neurological system and the immune system.AimsThe aim of the study was to determine whether and in what form the addition of copper changes the level of amyloid beta and acetylcholinesterase level in selected rat tissues.MethodsThirty, healthy, male, albino Wistar rats aged 7 weeks were randomly divided into 3 groups. Three experimental treatments were used to evaluate the effects of different levels and sources of Cu (6.5 mg kg of diet) in the diet: Cu₀ – rats fed a diet without Cu supplementation; Cu_salt – rats fed a diet with CuCO₃ (6.5 mg kg of diet) during two months of feeding; Cu_NPs - rats fed a diet with Cu nanoparticles (6.5 mg kg of diet) during two months of feeding. In blood serum and tissue homogenates there rated the indicators proving the potential neurodegenerative effect and epigenetic DNA damage induced by chemical form of copper or lack of additional copper supplementation in diet were determined. There were analysed: level of acetylcholinesterase, β-amyloid, low-density lipoprotein receptor-related protein 1, apyrimidinic endonuclease, thymidine glycosidase, alkylpurine-DNA-N-glycosylase and glycosylated acetylcholinesterase.ResultsIrrespective of the form of copper added, it was found to increase acetylcholinesterase level in the brain, spleen and liver, as well as in the blood plasma of the rats. Copper in the form of CuCO₃ was found to increase acetylcholinesterase level in the kidneys. The addition of both forms of copper caused a marked increase in the plasma concentration of β-amyloid in comparison with the diet with no added Cu. The addition of both forms of copper caused a marked increase in the plasma concentration of β-amyloid in comparison with the diet with no added Cu.ConclusionsA lack of added Cu in the diet of rats reduces the concentration of amyloid-β in the blood, whereas administration of copper, in the form of either CuNPs or CuCO₃, increases the level of this peptide in the blood. The use of copper in the form of CuNPs in the diet of rats does not increase the level of β-amyloid more than the use of the carbonate form of this element. The use of CuNPs or CuCO₃ in the diet of rats increases acetylcholinesterase level in the brain, spleen, liver, and blood. CuNPs in the diet of rats were not found to increase acetylcholinesterase level to a greater extent than Cu⁺² carbonate.     

Effect of chromium methionine supplementation on lactation performance,hepatic respiratory rate and anti-oxidative capacity in early-lactating dairy cows

Chromium may regulate dairy cow metabolism; a chelated formation of chromium methionine (Cr-Met) is available to the feed industry. The objective of this study was to investigate the effect of Cr-Met supplementation on lactation performance, hepatic respiratory rate and anti-oxidative capacity in early-lactating Holstein dairy cows. 64 multiparous cows were assigned to 16 blocks based on parity and milk yield and then the four cows in a block were randomly allocated to four treatment groups with 0, 4, 8 or 16 g/d of Cr-Met per cow supplemented to a basal diet. Cows were moved from an open dry lot to a naturally ventilated tie stall barn 2 weeks before treatment to adapt to this facility, fed and milked at 0630, 1400, and 1930 h every day. The experiment lasted for 12 weeks. Milk yield and composition were recorded weekly. Dry matter intake was measured every 2 weeks for a total of six times throughout the trial. The plasma variables were measured in weeks 4, 8 and 12 of the experiment. Supplementation of Cr-Met did not affect DM intake of cows. As the supplementation of Cr-Met increased, yields of milk, fat, energy corrected milk (P < 0.01) and lactose (P = 0.01) increased in a linear manner. In terms of plasma variables, insulin concentration decreased in a linear manner with Cr-Met supplementation. As for variables relating to hepatic respiration rate, concentrations of pyruvate and NAD in the plasma were increased in quadratic manners, and lactic dehydrogenase activity was linearly increased as Cr-Met feeding levels increased. Moreover, plasma glutathione peroxidase and superoxide dismutase activity were increased in a linear manner. In conclusion, our study suggested that Cr-Met supplementation improved lactation performance of early-lactating dairy cows through enhancing antioxidant capacity and hepatic cellular respiration.     

Nicotinamide riboside,an NAD+ precursor,attenuates the development of liver fibrosis in a diet-induced mouse model of liver fibrosis

ObjectiveLiver fibrosis is part of the non-alcoholic fatty liver disease (NAFLD) spectrum, which currently has no approved pharmacological treatment. In this study, we investigated whether supplementation of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor, can reduce the development of liver fibrosis in a diet-induced mouse model of liver fibrosis.MethodsMale C57BL/6 J mice were fed a low-fat control (LF), a high-fat/high-sucrose/high-cholesterol control (HF) or a HF diet supplemented with NR at 400 mg/kg/day (HF-NR) for 20 weeks. Features of liver fibrosis were assessed by histological and biochemical analyses. Whole-body energy metabolism was also assessed using indirect calorimetry. Primary mouse and human hepatic stellate cells were used to determine the anti-fibrogenic effects of NR in vitro.ResultsNR supplementation significantly reduced body weight of mice only 7 weeks after mice were on the supplementation, but did not attenuate serum alanine aminotransferase levels, liver steatosis, or liver inflammation. However, NR markedly reduced collagen accumulation in the liver. RNA-Seq analysis suggested that the expression of genes involved in NAD+ metabolism is altered in activated hepatic stellate cells (HSCs) compared to quiescent HSCs. NR inhibited the activation of HSCs in primary mouse and human HSCs. Indirect calorimetry showed that NR increased energy expenditure, likely by upregulation of β-oxidation in skeletal muscle and brown adipose tissue.ConclusionNR attenuated HSC activation, leading to reduced liver fibrosis in a diet-induced mouse model of liver fibrosis. The data suggest that NR may be developed as a potential preventative for human liver fibrosis.     

Amelioration of hyperglycaemia and hyperlipidaemia by adjusting the interplay between gut microbiota and bile acid metabolism: Radix Scutellariae as a case

BackgroundOur previous clinical research showed that the interaction between gut microbiota and bile acids (BAs) in patients with type 2 diabetes mellitus (T2DM) changed significantly. We hypothesized that T2DM could be improved by adjusting this interaction mediated by farnesoid X receptor (FXR). T2DM belongs to the category of “xiaoke” in traditional Chinese medicine. Radix scutellariae has the effects of clearing away heat and eliminating dampness, curing jaundice and quenching thirst and is widely used alone or in combination with other medicines for the treatment of T2DM in China and throughout Asia. Additionally, the interaction between Radix scutellariae and gut microbiota may influence its efficacy in the treatment of T2DM.PurposeThis study chose Radix scutellariae to validate that T2DM could improve by adjusting the interaction between gut microbiota and bile acid metabolism.Study design and methodsRadix scutellariae water extract (WESB) was administered to a T2DM rat model established by a high-fat diet combined with streptozotocin. The body weight and blood glucose and insulin levels were measured. The levels of serum lipids, creatinine, uric acid, albumin and total bile acid were also detected. Changes in the pathology and histology of the pancreas, liver and kidney were observed by haematoxylin-eosin staining. The 16S rRNAs of gut microbiota were sequenced, and the faecal and serum BAs were determined by liquid chromatography tandem mass spectrometry. The expression levels of BA metabolism-associated proteins in the liver and intestine were evaluated by immunoblot analysis.ResultsThe results showed that WESB improved hyperglycaemia, hyperlipaemia, and liver and kidney damage in T2DM rats. In addition, the abundances of key gut microbiota and the concentrations of certain secondary BAs in faeces and serum were restored. Moreover, there was a significant correlation between the restored gut microbiota and BAs, which might be related to the activation of liver cholesterol 7α-hydroxylase (CYP7A1) and the inhibition of FXR expression in the intestine rather than the liver.ConclusionsThis study provided new ideas for the prevention or treatment of clinical diabetes and its complications by adjusting the interaction between gut microbiota and bile acid metabolism.     

A high-fat diet and high-fat and high-cholesterol diet may affect glucose and lipid metabolism differentially through gut microbiota in mice

This study was conducted to investigate the effects of a high-fat diet (HFD) and high-fat and high-cholesterol diet (HFHCD) on glucose and lipid metabolism and on the intestinal microbiota of the host animal. A total of 30 four-week-old female C57BL/6 mice were randomly divided into three groups (n=10) and fed with a normal diet (ND), HFD, or HFHCD for 12 weeks, respectively. The HFD significantly increased body weight and visceral adipose accumulation and partly lowered oral glucose tolerance compared with the ND and HFHCD. The HFHCD increased liver weight, liver fat infiltration, liver triglycerides, and liver total cholesterol compared with the ND and HFD. Moreover, it increased serum high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol compared with the ND and HFD and upregulated alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase significantly. The HFHCD also significantly decreased the α-diversity of the fecal bacteria of the mice, to a greater extent than the HFD. The composition of fecal bacteria among the three groups was apparently different. Compared with the HFHCD-fed mice, the HFD-fed mice had more Oscillospira, Odoribacter, Bacteroides, and [Prevotella], but less [Ruminococcus] and Akkermansia. Cecal short-chain fatty acids were significantly decreased after the mice were fed the HFD or HFHCD for 12 weeks. Our findings indicate that an HFD and HFHCD can alter the glucose and lipid metabolism of the host animal differentially; modifications of intestinal microbiota and their metabolites may be an important underlying mechanism.