Protein succinylation,hepatic metabolism,and liver diseases

Succinylation is a highly conserved post-translational modication that is processed via enzymatic and non-enzymatic mechanisms.Succinylation exhibits strong effects on protein stability,enzyme activity,and transcriptional regulation.Protein succinylation is extensively present in the liver,and increasing evidence has demonstrated that succinylation is closely related to hepatic metabolism.For instance,histone acetyltransferase 1 promotes liver glycolysis,and the sirtuin 5-induced desuccinylation is involved in the regulation of the hepatic urea cycle and lipid metabolism.Therefore,the effects of succinylation on hepatic glucose,amino acid,and lipid metabolism under the action of various enzymes will be discussed in this work.In addition,how succinylases regulate the progression of different liver diseases will be reviewed,including the desuccinylation activity of sirtuin 7,which is closely associated with fatty liver disease and hepatitis,and the actions of lysine acetyltransferase 2A and histone acetyltransferase 1 that act as succinyltransferases to regulate the succinylation of target genes that influence the development of hepatocellular carcinoma.In view of the diversity and significance of protein succinylation,targeting the succinylation pathway may serve as an attractive direction for the treatment of liver diseases.

Fibroblast growth factor 15,induced by elevated bile acids,mediates the improvement of hepatic glucose metabolism after sleeve gastrectomy

BACKGROUND Fibroblast growth factor(FGF)15/19,which is expressed in and secreted from the distal ileum,can regulate hepatic glucose metabolism in an endocrine manner.The levels of both bile acids(BAs)and FGF15/19 are elevated after bariatric surgery.However,it is unclear whether the increase in FGF15/19 is induced by BAs.Moreover,it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery.AIM To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy(SG).METHODS By calculating and comparing the changes of body weight after SG with SHAM group,we examined the weight-loss effect of SG.The oral glucose tolerance test(OGTT)test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG.By detecting the glycogen content,expression and activity of glycogen synthase as well as the glucose-6-phosphatase(G6Pase)and phosphoenolpyruvate carboxykinase(Pepck),we evaluated the hepatic glycogen content and gluconeogenesis activity.We examined the levels of total BA(TBA)together with the farnesoid X receptor(FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery.Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4(FGFR4)with its corresponding signal pathways involved in glucose metabolism were detected.RESULTS After surgery,food intake and body weight gain of SG group was decreased compare with the SHAM group.The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG,while the expression of the key enzyme for hepatic gluconeogenesis:G6Pase and Pepck,were depressed.TBA levels in serum and portal vein were both elevated after SG,the FXR-agonistic BA subspecies:Chenodeoxycholic acid(CDCA),lithocholic acid(LCA)in serum and CDCA,DCA,LCA in portal vein were all higher in SG group than that in SHAM group.Consequently,the ileal expression of FXR and FGF15 were also advanced in SG group.Moreover,the hepatic expression of FGFR4 was stimulated in SG-operated rats.As a result,the activity of its corresponding pathway for glycogen synthesis:FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated,while the corresponding pathway for hepatic gluconeogenesis:FGFR4-cAMP regulatory element-binding protein-peroxisome proliferator-activated receptorγcoactivator-1αpathway was suppressed.CONCLUSION Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR.Furthermore,the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG.

Secreted Frizzled-Related Protein 5 Mediates Wnt5a Expression in Microcystin-Leucine-Arginine-Induced Liver Lipid Metabolism Disorder in Mice

Objective Microcystin-leucine-arginine(MC-LR)exposure induces lipid metabolism disorders in the liver.Secreted frizzled-related protein 5(SFRP5)is a natural antagonist of winglesstype MMTV integration site family,member 5A(Wnt5a)and an anti-inflammatory adipocytokine.In this study,we aimed to investigate whether MC-LR can induce lipid metabolism disorders in hepatocytes and whether SFRP5,which has anti-inflammatory effects,can alleviate the effects of hepatic lipid metabolism by inhibiting the Wnt5a/Jun N-terminal kinase(JNK)pathway.Methods We exposed mice to MC-LR in vivo to induce liver lipid metabolism disorders.Subsequently,mouse hepatocytes that overexpressed SFRP5 or did not express SFRP5 were exposed to MC-LR,and the effects of SFRP5 overexpression on inflammation and Wnt5a/JNK activation by MC-LR were observed.Results MC-LR exposure induced liver lipid metabolism disorders in mice and significantly decreased SFRP5 mRNA and protein levels in a concentration-dependent manner.SFRP5 overexpression in AML12cells suppressed MC-LR-induced inflammation.Overexpression of SFRP5 also inhibited Wnt5a and phosphorylation of JNK.Conclusion MC-LR can induce lipid metabolism disorders in mice,and SFRP5 can attenuate lipid metabolism disorders in the mouse liver by inhibiting Wnt5a/JNK signaling.

Selenogenome and AMPK signal insight into the protective effect of dietary selenium on chronic heat stress-induced hepatic metabolic disorder in growing pigs

Background:Chronic heat stress(CHS)disrupts hepatic metabolic homeostasis and jeopardizes product quality of pigs.Selenium(Se)may regulate the metabolic state through affect selenoprotein.Thus,we investigate the protective effect of dietary hydroxy-4-methylselenobutanoic acid(HMSeBA)on CHS induced hepatic metabolic disorder in growing pigs,and the corresponding response of selenoprotein.Methods:Forty crossbreed growing pigs were randomly assigned to five groups:control group raised in the thermoneutral environment(22±2℃)with basal diet;four CHS groups raised in hyperthermal condition(33±2℃)with basal diet and supplied with 0.0,0.2,0.4,and 0.6 mg Se/kg HMSeBA,respectively.The trial lasted 28 d.The serum biochemical,hepatic metabolism related enzyme,protein and gene expression and 25 selenoproteins in liver tissue were determined by real-time PCR,ELISA and western blot.Results:CHS significantly increased the rectal temperature,respiration rate,serum aspartate aminotransferase(AST)and low-density lipoprotein cholesterol(LDL-C)of pigs,up-regulated hepatic heat shock protein 70(HSP70)and induced lower liver weight,glycogen content,hepatic glucokinase and glutathione peroxidase(GSH-Px).The CHSinduced liver metabolic disorder was associated with the aberrant expression of 6 metabolism-related gene and 11 selenoprotein encoding genes,and decreased the protein abundance of GCK,GPX4 and SELENOS.HMSeBA improved anti-oxidative capacity of liver.0.4 or 0.6 mg Se/kg HMSeBA supplementation recovered the liver weight,glycogen content and rescue of mRNA abundance of genes related to metabolism and protein levels of GCK.HMSeBA supplementation changed expressions of 15 selenoprotein encoding genes,and enhanced protein expression of GPX1,GPX4 and SELENOS in the liver affected by CHS.CHS alone showed no impact while HMSeBA supplementation increased protein levels of p-AMPKαin the liver.Conclusions:In summary,HMSeBA supplementation beyond nutrient requirement mitigates CHS-induced hepatic metabolic disorder,recovered the liver glycogen content and the processes that are associated with the activation of AMPK signal and regulation of selenoproteins in the liver of growing pigs.

Glucuronidation is the dominating in-vivo metabolism pathway of herbacetin:elucidation of herbacetin pharmacokinetics after intravenous and oral administration in rats

OBJECTIVE To map a comprehensive metabolic pathway of herbacetin in rats,specifically,to elucidate the biotransformation of herbacetin in vivo and to simultaneously monitor the pharmacokinetic process of both parent drug and its major metabolites.METHODS liquid chromatography/ion trap mass spectrometry(LC/MS n) and ultra-liquid chromatography coupled with mass spectrometry(UPLC/MS) were combined in the current study for qualitative and quantitative determinations of herbacetin and its metabolites in bile,urine and feces after both oral and intravenous administration of herbacetin to rats.Enzyme kinetic studies on the intestinal and hepatic metabolism of herbacetin were further conducted to elucidate metabolic profiles of herbacetin in rat tissues and organs.Additionally,plasma concentration profiles of herbacetin and its metabolites in rats were obtained to characterize the overall pharmacokinetic behavior of herbacetin.RESULTS It was found that herbacetin was excreted primarily from rat urine in the form of glucuronide-conjugations.Subsequent in vitro enzyme kinetic studies and in vivo pharmacokinetic investigations suggested an extensive hepatic metabolism of herbacetin and the high exposure of herbacetin-glucuronides in systemic circulation.The clearance,half-life and bioavailability of herbacetin in rats were determined as(16.4±1.92)mL·kg^(-1)·min^(-1),(11.9±2.7)min,and 1.32%,respectively.On basis of these findings,a comprehensive metabolic pathway of herbacetin in rats was composed.In addition,a physiology based pharmacokinetic(PBPK) model was successfully developed with the aid of the Gastro Plus to simulate the pharmacokinetic process of herbacetin in rats.Application of the PBPK modeling can provide a useful starting point to understand and extrapolate pharmacokinetic parameters among different species,populations,and disease states.CONCLUSION After oral administration,herbacetin was subjected to colonic degradation and extensive first pass metabolism,with glucuronidation as its dominating in vivo metabolic pathway.

Changes in lipid metabolism in chronic hepatitis C

AIM: To investigate the relationship between certain biochemical parameters of lipid metabolism in the serum and steatosis in the liver.METHODS: The grade of steatosis (0-3) and histological activity index (HAI, 0-18) in liver biopsy specimens were correlated with serum alanine aminotransferase (ALT), total cholesterol and triglyceride levels in 142 patients with chronic hepatitis C (CH-C), and 28 patients with non-alcoholic fatty liver disease (NAFLD) without hepatitis C virus (HCV) infection. The serum parameters were further correlated with 1 797 age and sex matched control patients without any liver diseases.RESULTS: Steatosis was detected in 90 out of 142 specimens (63%) with CH-C. The ALT levels correlated with the grade of steatosis, both in patients with CH-C and NAFLD (P＜0.01). Inserting the score values of steatosis as part of the HAI, correlation with the ALT level (P＜0.00001) was found. The triglyceride and cholesterol levels were significantly lower in patients with CH-C (with and without steatosis), compared to the NAFLD group and to the virus-free control groups.CONCLUSION: Our study confirms the importance of liver steatosis in CH-C which correlates with lower lipid levels in the sera. Inclusion of the score of steatosis into HAI, in case of CH-C might reflect the alterations in the liver tissue more precisely, while correlating with the ALT enzyme elevation.

The Action of p-Synephrine on Lipid Metabolism in the Perfused Rat Liver

p-synephrine and p-octopamine were found to increase lipolysis in adipocytes. The present study approaches the question if these compounds, natural products of the bitter orange (Citrus aurantium fruit), increase lipolysis and fatty acid oxidation in the liver. Experiments were done in the perfused rat liver. Non-recirculating hemoglobin-free perfusion was done using the Krebs/ Henseleit-bicarbonate buffer (pH 7.4) as perfusion fluid. Both p-synephrine and p-octopamine, at the concentrations of 100 μM, were found to stimulate the hepatic triacylglycerol lipase by 40% and 51%, respectively. These seem to be the maximal stimulations possible in the liver. In the perfused liver, p-synephrine, when present at an initial concentration of 500 μM, was able to increase the non-esterified fatty acid release after one hour of recirculating perfusion. The effects of p-synephrine on the oxidation of exogenously supplied [1-14C]octanoate and [1-14C]oleate were minimal. Only oxygen uptake, already stimulated by octanoate or oleate, was additionally increased by the infusion of p-synephrine. These results contrast with those obtained in a previous study with p-octopamine, which increased the production of 14CO2 from both [1-14C]octanoate and [1-14C]oleate. Apparently only the oxidation of endogenous fatty acids is stimulated by p-synephrine. On the other hand, both p-synephrine and p-octopamine stimulate the hepatic triacylglycerol lipase to a much lesser extent than the adipocyte lipase. It can be concluded that p-synephrine affects much more carbohydrate metabolism in the liver than lipid metabolism.

Dietary pattern and hepatic lipid metabolism

The liver is the leading site for lipid metabolism,involving not only fatty acid beta-oxidation but also de novo synthesis of endogenous triglycerides and ketogenesis.The liver maintains systemic lipid homeostasis by regulating lipid synthesis,catabolism,and transportation.Dysregulation of hepatic lipid metabolism precipitates disorders,such as non-alcoholic fatty liver disease(NAFLD),affecting the whole body.Thus,comprehending and studying hepatic lipid metabolism is crucial for preventing and treating metabolic liver diseases.Traditionally,researchers have investigated the impact of a single nutrient on hepatic lipid metabolism.However,real-life dietary patterns encompass diverse nutrients rather than single components.In recent years,there have been increased studies and notable progress regarding the effects of distinct dietary patterns on hepatic lipid metabolism.This review summarizes the influence of diverse dietary patterns on hepatic lipid metabolism,elucidating underlying molecular mechanisms and appraising the therapeutic potential of dietary patterns in managing hepatic steatosis.

Inhibitory effect of schisandrin B on free fatty acid-induced steatosis in L-02 cells

AIM:To investigate the effects of schisandrin B (Sch B) on free fatty acid (FFA)-induced steatosis in L-02 cells.METHODS:Cellular steatosis was induced by incubating L-02 cells with a FFA mixture (oleate and palmitate at the ratio of 2:1) for 24 h.Cytotoxicity and apoptosis were evaluated by 3-(4,5-dmethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and Annexin V/propidium iodide staining,respectively.Cellular total lipid was determined using a photocolorimetric method after Nile red staining,and triglyceride content was measured using an enzymatic kit.To study the effects of Sch B on steatosis,L-02 cells were treated with Sch B (1-100 μmol/L) in the absence or presence of 1 mmol/L FFA for 24 h,and cellular total lipid and triglyceride levels were measured.To explore the mechanisms of action of Sch B in the steatotic L-02 cells,mRNA levels of several regulators of hepatic lipid metabolism including adipose differentiation related protein (ADRP),sterol regulatory element binding protein 1 (SREBP-1),peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ were measured by quantitative real-time polymerase chain reaction (PCR),and protein levels of ADRP and SREBP-1 were measured by immunoblotting.RESULTS:Treatment with 1 mmol/L FFA for 24 h induced intracellular lipid accumulation in L-02 cells comparable to that in human steatotic livers without causing apparent apoptosis and cytotoxicity.Sch B mitigated cellular total lipid and triglyceride accumulations in the steatotic L-02 cells in a dose-dependent manner.Quantitative real-time PCR and Western blot analyses revealed that treatment of L-02 cells with 100 μmol/L Sch B reverted the FFA-stimulated up-regulation of ADRP and SREBP-1.CONCLUSION:Sch B inhibits FFA-induced steatosis in L-02 cells by,at least in part,reversing the up-regulation of ADRP and SREBP-1.

Dietary glutamine,glutamate,and aspartate supplementation improves hepatic lipid metabolism in post-weaning piglets

A previous study has demonstrated that early weaning significantly suppressed hepatic glucose metabolism in piglets.Glutamate(Glu),aspartate(Asp)and glutamine(Gln)are major metabolic fuels for the small intestine and can alleviate weaning stress,and therefore might improve hepatic energy metabolism.The objective of this study was to investigate the effects of administration of Glu,Asp and Gln on the expression of hepatic genes and proteins involved in lipid metabolism in post-weaning piglets.Thirty-six weaned piglets were assigned to the following treatments:control diet(Control;basal diet+15.90 g/kg alanine);Asp,Gln and Glu-supplemented diet(Control+AA;basal diet+1.00 g/kg Asp+5.00 g/kg Glu+10.00 g/kg Gln);and the energy-restricted diet supplemented with Asp,Gln and Glu(Energy^-+AA;energy deficient diet+1.00 g/kg Asp+5.00 g/kg Glu+10.00 g/kg Gln),Liver samples were obtained on d 5 and 21 post-weaning.Piglets fed Energy^-+AA diet had higher liver mRNA abundances of acyl-CoA oxidase 1(ACOX1),succinate dehydrogenase(SDH),mitochondrial transcription factor A(TFAM)and sirtuin 1(SIRT1),as well as higher protein expression of serine/threonine protein kinase 11(LKB1),phosphor-acetyl-CoA carboxylase(P-ACC)and SIRT1 compared with piglets fed control diet(P<0.05)on d 5 post-weaning.Control+AA diet increased liver malic enzyme 1(ME1)and SIRT1 mRNA levels,as well as protein expression of LKBl and P-ACC on d 5 post-weaning(P<0.05).On d 21 post-weaning,compared to control group,Glu,Gln and Asp supplementation up-regulated the mRNA levels of ACOX1,ME1 and SIRT1(P<0.05).These findings indicated that dietary Glu,Gln and Asp supplementation could improve hepatic lipid metabolism to some extent,which may provide nutritional intervention for the insufficient energy intake after weaning in piglets.

Glycogenotic hepatocellular carcinoma with glycogen-ground-glass hepatocytes: A heuristically highly relevant phenotype

Glycogenotic hepatocellular carcinoma (HCC) with glycogen-ground-glass hepatocytes has recently been described as an allegedly "novel variant" of HCC, but neither the historical background nor the heuristic relevance of this observation were put in perspective. In the present contribution, the most important findings in animal models and human beings related to the emergence and further evolution of excessively glycogen storing (glycogenotic) hepatocytes with and without ground glass features during neoplastic development have been summarized. Glycogenotic HCCs with glycogen-ground-glass hepatocytes represent highly differentiated neoplasms which contain subpopulations of cells phenotypically resembling those of certain types of preneoplastic hepatic foci and benign hepatocellular neoplasms. It is questionable whether the occurrence of glycogen-ground-glass hepatocytes in a glycogenotic HCC justifies its classification as a specific entity. The typical appearance of ground-glass hepatocytes is due to a hypertrophy of the smooth endoplasmic reticulum, which is usually associated with an excessive storage of glycogen and frequently also with an expression of the hepatitis B surface antigen. Sequential studies in animal models and observations in humans indicate that glycogen-ground-glass hepatocytes are a facultative, integral part of a characteristic cellular sequence commencing with focal hepatic glycogenosis potentially progressing to benign and malignant neoplasms. During this process highly differentiated glycogenotic cells including ground-glass hepatocytes are gradually transformed via various intermediate stages into poorly differentiated glycogen-poor, basophilic (ribosome-rich) cancer cells. Histochemical, microbiochemical, and molecular biochemical studies on focal hepatic glycogenosis and advanced preneoplastic and neoplastic lesions in tissue sections and laser-dissected specimens in rat and mouse models have provided compelling evidence for an early insulinomimetic effect of oncogenic agents, which is followed by a fundamental metabolic switch from gluconeogenesis towards the pentose-phosphate pathway and the Warburg type of glycolysis during progression from preneoplastic hepatic glycogenosis to the highly proliferative malignant phenotype.

Effects of Bacillus subtilis on hepatic lipid metabolism and oxidative shess response in grass carp(Ctenopharyngodon idellus)fed a high-fat diet

Bacillus subtilis is widely used in aquaculture as a probiotic.However,few studies have been conducted to examine the effect of B.subtilis on liver lipid metabolism.A total of 135 healthy grass carp(50.24±1.38 g)were randomly divided into three groups:control(Con),high-fat diet(HF),and high-fat diet+B.subtilis(HF4-B.subtilis),and fed for 8 weeks.The results showed that compared with the HF group,the weight gain rate(WGR)significantly increased(Pc0.05)and the hepatic lipid content,serum low-density lipoprotein cholesterol(LDL-C),and aspartate aminotransferase(AST)decreased in the group supplemented with B.subtilis(P<0.05).Moreover,the hepatic mRNA expression of fatty acid synthase(FAS)was significantly down-regulated and the carnitine palmitoyl transferases(CPTlala)were up-regulated in the HF+B.subtilis group compared to the HF group(P<0.05),respectively.Additionally,in the HF+B.subtilis group,glutathione(GSH)significantly increased(Pv 0.()5),while hydrogen peroxide(H2O2)and malondialdehyde(MDA)contents significantly decreased compared to the HF group(P v0.05).B.subtilis may reduce the hepatic lipid content by inhibiting its synthesis and promoting p-oxidation of fatty acids.B.subtilis may also alleviate dyslipidaemia and prevent oxidative damage in the liver caused by the high-fat diet of grass carp.Hence,dietary supplementation with B.subtilis shows promise as a therapeutic or preventive tool against fatty liver disease.

Influence of Phenobarbital and Carbon tetrachloride on the Modulation of Tissue Retention Profile of Hexachlorocyclohexane in Rats

The study was designed to investigate the role of hepatic metabolic activity on body burden of HCH residue. Male albino rats were orally administered 0, 5, and 10 mg/kg HCH for 90 days, followed by either sodium phenobarbital or carbon tetrachloride treatment for 0, 15 and 30 days after withdrawal of their respective HCH administration. The liver weight was significantly increased at 30 days after the administration of phenobarbital and carbon tetrachloride in both 5 mg and 10 mg/kg HCH withdrawal groups when compared to control. HCH residue was maximun in fat followed by adrenal>thymus>liver>kidney>spleen>testes>brain>plasma. Carbon tetrachloride caused an accumul-ation of HCH residues in the liver 15 and 30 days after administration of both doses of HCH. Phenobarbital did not show significant variation in HCH residues in hepatic tissue. Phenobarbital treatment caused significant induction of hepatic RED, APD, AHH, GST and QR activities. Significant decreases in activities were observed by carbon tetrachloride when compared to animals treated with HCH alone. The overall results clearly suggest the role of P450 protein on the body burden of HCH residues.

Highly expressed BMP9/GDF2 in postnatal mouse liver and lungs may account for its pleiotropic effects on stem cell differentiation,angiogenesis,tumor growth and metabolism

Bone morphogenetic protein 9(BMP9)(or GDF2)was originally identified from fetal mouse liver cDNA libraries.Emerging evidence indicates BMP9 exerts diverse and pleiotropic functions during postnatal development and in maintaining tissue homeostasis.However,the expression landscape of BMP9 signaling during development and/or in adult tissues remains to be analyzed.Here,we conducted a comprehensive analysis of the expression landscape of BMP9 and its signaling mediators in postnatal mice.By analyzing mouse ENCODE transcriptome datasets we found Bmp9 was highly expressed in the liver and detectable in embryonic brain,adult lungs and adult placenta.We next conducted a comprehensive qPCR analysis of RNAs isolated from major mouse tissues/organs at various ages.We found that Bmp9 was highly expressed in the liver and lung tissues of young adult mice,but decreased in older mice.Interestingly,Bmp9 was only expressed at low to modest levels in developing bones.BMP9-associated TGFβ/BMPR type I receptor Alk1 was highly expressed in the adult lungs.Furthermore,the feedback inhibitor Smads Smad6 and Smad7 were widely expressed in mouse postnatal tissues.However,the BMP signaling antagonist noggin was highly expressed in fat and heart in the older age groups,as well as in kidney,liver and lungs in a biphasic fashion.Thus,our findings indicate that the circulating BMP9 produced in liver and lungs may account for its pleiotropic effects on postnatal tissues/organs although possible roles of BMP9 signaling in liver and lungs remain to be fully understood.

Effects of acute or prolonged exposure to leptin on hepatic glucose oxidation

Objective To observe the short-term and long-term effects of leptin on hepatic glucose oxidation and glucokinase gene expression. Methods Rat hepatic cell line BRL was incubated with leptin of different doses (range from 10?ng/ml-200?ng/ml) for 1?h or 24?h. Glucose oxidation was determined by liquid scintillation counting. Glucokinase gene expression (corrected by β-actin) was determined by reverse transcription semi-quantitative polymerase chain reaction. Results Treatment with leptin 10?ng/ml for 1?h had no significant effects on glucose oxidation in hepatic cells. However, at the doses ranging from 50?ng/ml to 200?ng/ml, leptin significantly inhibited glucose oxidation. These effects disappeared when the hepatic cells were exposed to leptin for 24?h. Glucokinase mRNA expression was reduced significantly after both 1?h and 24?h exposure to leptin (100?ng/ml) as compared to that of the control group. Conclusion A low dose of leptin has no significant effect on glucose oxidation in hepatic cells. A relatively high dose of leptin has an acute inhibitory effect on the glucose oxidation in hepatic cells. This effect may likely involve the inhibition of glucokinase gene expression. The inhibitory effect on glucose oxidation is transient and disappears with prolonged exposure time.

Exercise during weight loss improves hepatic mitophagy

Non-alcoholic fatty liver disease(NAFLD)has recently become a public health concern concurrent with the obesity crisis.Previous work has shown aberrant mitochondrial content/quality and autophagy in models of NAFLD,whereas exercise is known to improve these derangements.The purpose of this study was to examine the effect of different weight-loss modalities on hepatic mitochondrial content,autophagy and mitophagy in NAFLD.Forty-eight male C57BL/6J mice were divided into 1 of 4 groups:low fat diet(LFD,10%fat,18 weeks),high fat diet(HFD,60%fat diet,18 weeks),weight-loss by diet(D,60%fat diet for 10 weeks then 10%fat diet for 8 weeks)or weight-loss by diet and physical activity(D/PA,60%fat diet for 10 weeks,then 10%fat diet plus a running wheel for 8 weeks).Immunoblot data were analyzed by one-way analysis of variance(ANOVA)with significance denoted at p<0.05.COX-IV protein contents were approximately 50%less in HFD compared to LFD.D/PA had 50%more BNIP3 compared to HFD.PINK1 content was 40%higher in D and D/PA compared to LFD.PPARKIN/PARKIN levels were 40%lower in HFD,D,and D/PA compared to LFD.Whereas p-UbSer65 was 3-fold higher in HFD.LC3II/I ratio was 50%greater in HFD and D/PA,yet p62 protein content was 2.5 fold higher in HFD.High-fat diet causes disruptions in markers of mitochondrial quality control.Physical activity combined with diet were able to ameliorate these derangements and seemingly improve hepatic mitochondrial quality above control values.

Interaction between stress responses and circadian metabolism in metabolic disease

Circadian rhythms play crucial roles in orchestrating diverse physiological processes that are critical for health and disease.Dysregulated circadian rhythms are closely associated with various human metabolic diseases,including type 2 diabetes,cardiovascular disease,and non-alcoholic fatty liver disease.Modern lifestyles are frequently associated with an irregular circadian rhythm,which poses a significant risk to public health.While the central clock has a set periodicity,circadian oscillators in peripheral organs,particularly in the liver,can be entrained by metabolic alterations or stress cues.At the molecular level,the signal transduction pathways that mediate stress responses interact with the key determinants of circadian oscillation to maintain metabolic homeostasis under physiological or pathological conditions.In the liver,a number of nuclear receptors or transcriptional regulators,which are regulated by metabolites,hormones,the circadian clock,or environmental stressors,serve as direct links between stress responses and circadian metabolism.In this review,we summarize recent advances in the understanding of the interactions between stress responses(endoplasmic reticulum stress response,oxidative stress response,and inflammatory responses)and circadian metabolism,and the role of these interactions in the development of metabolic diseases.

Dynamic carbon 13 breath tests for the study of liver function and gastric emptying

In gastroenterological practice,breath tests(BTs)are diagnostic tools used for indirect,non-invasive assessment of several pathophysiological metabolic processes,by monitoring the appearance in breath of a metabolite of a specific substrate.Labelled substrates originally employed radioactive carbon 14(^(14)C)and,more recently,the stable carbon 13 isotope(^(13)C)has been introduced to label specific substrates.The ingested^(13)C-substrate is metabolized,and exhaled^(13)CO_(2)is measured by mass spectrometry or infrared spectroscopy.Some^(13)C-BTs evaluate specific(microsomal,cytosolic,and mitochondrial)hepatic metabolic pathways and can be employed in liver diseases(i.e.simple liver steatosis,non-alcoholic steato-hepatitis,liver fibrosis,cirrhosis,hepatocellular carcinoma,drug and alcohol effects).Another field of clinical application for^(13)C-BTs is the assessment of gastric emptying kinetics in response to liquids(^(13)C-acetate)or solids(^(13)C-octanoic acid in egg yolk or in a pre-packed muffin or the^(13)C-Spirulina platensis given with a meal or a biscuit).Studies have shown that^(13)C-BTs,used for gastric emptying studies,yield results that are comparable to scintigraphy and can be useful in detecting either delayed-(gastroparesis)or accelerated gastric emptying or changes of gastric kinetics due to pharmacological effects.Thus,^(13)C-BTs represent an indirect,cost-effective and easy method of evaluating dynamic liver function and gastric kinetics in health and disease,and several other potential applications are being studied.

Integrated liver proteomics and metabolomics identify metabolic pathways affected by pantothenic acid deficiency in Pekin ducks

Pantothenic acid deficiency(PAD)in animals causes growth depression,fasting hypoglycemia and impaired lipid and glucose metabolism.However,a systematic multi-omics analysis of effects of PAD on hepatic function has apparently not been reported.We investigated liver proteome and metabolome changes induced by PAD to explain its effects on growth and liver metabolic disorders.Pekin ducks(1-dold,n=128)were allocated into 2 groups,with 8 replicates and 8 birds per replicate.For 16 d,all ducks had ad libitum access to either a PAD or a pantothenic acid adequate(control,CON)diet,formulated by supplementing a basal diet with 0 or 8 mg pantothenic acid/kg of diet,respectively.Liver enlargement,elevated liver glycogen concentrations and decreased liver concentrations of triglyceride and unsaturated fatty acids were present in the PAD group compared to the CON group.Based on integrated liver proteomics and metabolomics,PAD mainly affected glycogen synthesis and degradation,glycolysis and gluconeogenesis,tricarboxylic acid(TCA)cycle,peroxisome proliferator-activated receptor(PPAR)signaling pathway,fatty acid beta oxidation,and oxidative phosphorylation.Selected proteins were confirmed by Western blotting.Downregulation of proteins and metabolites involved in glycogen synthesis and degradation,glycolysis and gluconeogenesis implied that these processes were impaired in PAD ducks,which could have contributed to fasting hypoglycemia,liver glycogen storage,insufficient ATP production,and growth retardation.In contrast,PAD also upregulated proteins and metabolites involved in fatty acid beta oxidation,the TCA cycle,and oxidative phosphorylation processes in the liver;presumably compensatory responses to produce ATP.We inferred that PAD decreased liver triglyceride and unsaturated fatty acids by activating fatty acid beta oxidation and impairing unsaturated fatty acid synthesis.These findings contributed to our understanding of the mechanisms of PAD-induced changes in hepatic metabolism.

New insight into inter-organ crosstalk contributing to the pathogenesis of non- alcoholic fatty liver disease （NAFLD）

Non-alcoholic fatty liver disease （NAFLD） is the most common cause of chronic liver dysfunction and a sig- nificant global health problem with substantial rise in prevalence over the last decades. It is becoming increasingly clear that NALFD is not only predominantly a hepatic manifestation of metabolic syndrome, but also involves extra-hepatic organs and regulatory pathways. Therapeutic options are limited for the treatment of NAFLD. Accordingly, a better understanding of the pathogenesis of NAFLD is critical for gaining new insight into the regulatory network of NAFLD and for identifying new targets for the prevention and treatment of NAFLD. In this review, we emphasize on the current understanding of the inter-organ crosstalk between the liver and peripheral organs that contributing to the pathogenesis of NAFLD.