Palmitoyltransferase Research Articles

The Chinese herbal medicine Fufang Zhenzhu Tiaozhi ameliorates diabetic cardiomyopathy by regulating cardiac abnormal lipid metabolism and mitochondrial dynamics in diabetic mice

Diabetic cardiomyopathy (DCM) is an important complication leading to the death of patients with diabetes, but there is no effective strategy for clinical treatments. Fufang Zhenzhu Tiaozhi (FTZ) is a patent medicine that is a traditional Chinese medicine compound preparation with comprehensive effects for the prevention and treatment of glycolipid metabolic diseases under the guidance of “modulating liver, starting pivot and cleaning turbidity”. FTZ was proposed by Professor Guo Jiao and is used for the clinical treatment of hyperlipidemia. This study was designed to explore the regulatory mechanisms of FTZ on heart lipid metabolism dysfunction and mitochondrial dynamics disorder in mice with DCM, and it provides a theoretical basis for the myocardial protective effect of FTZ in diabetes. In this study, we demonstrated that FTZ protected heart function in DCM mice and downregulated the overexpression of free fatty acids (FFAs) uptake-related proteins cluster of differentiation 36 (CD36), fatty acid binding protein 3 (FABP3) and carnitine palmitoyl transferase 1 (CPT1). Moreover, FTZ treatment showed a regulatory effect on mitochondrial dynamics by inhibiting mitochondrial fission and promoting mitochondrial fusion. We also identified in vitro that FTZ could restore lipid metabolism-related proteins, mitochondrial dynamics-related proteins and mitochondrial energy metabolism in PA-treated cardiomyocytes. Our study indicated that FTZ improves the cardiac function of diabetic mice by attenuating the increase in fasting blood glucose levels, inhibiting the decrease in body weight, alleviating disordered lipid metabolism, and restoring mitochondrial dynamics and myocardial apoptosis in diabetic mouse hearts.

Intermittent Fasting Sustainably Improves Glucose Tolerance in Normal Weight Male Mice Through Histone Hyperacetylation

Abstract To explore the mechanism by which intermittent fasting (IF) exerts prolonged effects after discontinuation, we examined mice that had been subjected to 4 cycles of fasting for 72 hours and ad libitum feeding for 96 hours per week (72hIF), followed by 4 weeks of ad libitum feeding, focusing on expression of genes for lipid metabolism in the skeletal muscle and histone acetylation in the promoter region. The 72hIF regimen resulted in metabolic remodeling, characterized by enhanced lipid utilization and mitochondrial activation in the muscle. This long-term IF (72hIF) caused stronger metabolic effects than alternate day fasting (24hIF) wherein fasting and refeeding are repeated every 24 hours. Upregulation of lipid oxidation genes and an increase in oxygen utilization were sustained even at 4 weeks after discontinuation of 72hIF, associated with histone hyperacetylation of the promoter region of uncoupling protein 3 (Ucp3) and carnitine palmitoyl transferase 1b (Cpt1b) genes. An increase in leucine owing to fasting-induced muscle degradation was suggested to lead to the histone acetylation. These findings support the previously unappreciated notion that sustainable promotion of histone acetylation in lipid oxidation genes of the muscle and adipose tissues during and after IF may contribute to sustained metabolic effects of IF.

Hepatic deletion of serine palmitoyl transferase 2 impairs ceramide/sphingomyelin balance, bile acids homeostasis and leads to liver damage in mice

Ceramides (Cer) have been shown as lipotoxic inducers, which disturb numerous cell-signaling pathways, leading to metabolic disorders such as type 2 diabetes. In this study, we aimed to determine the role of de novo hepatic ceramide synthesis in energy and liver homeostasis in mice. We generated mice lacking serine palmitoyltransferase 2 (Sptlc2), the rate limiting enzyme of ceramide de novo synthesis, in liver under albumin promoter. Liver function, glucose homeostasis, bile acid (BA) metabolism and hepatic sphingolipids content were assessed using metabolic tests and LC-MS. Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic Cer, associated with a 10-fold increase in neutral sphingomyelinase 2 (nSMase2) expression, and a decreased sphingomyelin content in the liver. Sptlc2ΔLiv mice were protected against obesity induced by high fat diet and displayed a defect in lipid absorption. In addition, an important increase in tauro-muricholic acid was associated with a downregulation of the nuclear BA receptor FXR target genes. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production, while the latter effect was dampened in presence of nSMase2 inhibitor. Finally, Sptlc2 disruption promoted apoptosis, inflammation and progressive development of hepatic fibrosis, worsening with age. Our data suggest a compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis, with deleterious impact on liver homeostasis. In addition, our results show the involvement of hepatic sphingolipid modulation in BA metabolism and hepatic glucose production in an insulin-independent manner, which highlight the still under-researched role of ceramides in many metabolic functions.

Increasing maternal age associates with lower placental CPT1B mRNA expression and acylcarnitines, particularly in overweight women.

Older pregnant women have increased risks of complications including gestational diabetes and stillbirth. Carnitine palmitoyl transferase (CPT) expression declines with age in several tissues and is linked with poorer metabolic health. Mitochondrial CPTs catalyze acylcarnitine synthesis, which facilitates fatty acid oxidization as fuel. We hypothesized that the placenta, containing maternally-inherited mitochondria, shows an age-related CPT decline that lowers placental acylcarnitine synthesis, increasing vulnerability to pregnancy complications. We assessed CPT1A, CPT1B, CPT1C and CPT2 mRNA expression by qPCR in 77 placentas and quantified 10 medium and long-chain acylcarnitines by LC-MS/MS in a subset of 50 placentas. Older maternal age associated with lower expression of placental CPT1B, but not CPT1A, CPT1C or CPT2. CPT1B expression positively associated with eight acylcarnitines and CPT1C with three acylcarnitines, CPT1A negatively associated with nine acylcarnitines, while CPT2 did not associate with any acylcarnitine. Older maternal age associated with reductions in five acylcarnitines, only in those with BMI≥ 25kg/m2, and not after adjusting for CPT1B expression. Our findings suggest that CPT1B is the main transferase for placental long-chain acylcarnitine synthesis, and age-related CPT1B decline may underlie decreased placental metabolic flexibility, potentially contributing to pregnancy complications in older women, particularly if they are overweight.

Ceramide present in cholangiocarcinoma-derived extracellular vesicle induces a pro-inflammatory state in monocytes

Cholangiocarcinoma (CCA) is a rare cancer characterized by a global increasing incidence. Extracellular vesicles (EV) contribute to many of the hallmarks of cancer through transfer of their cargo molecules. The sphingolipid (SPL) profile of intrahepatic CCA (iCCA)-derived EVs was characterized by liquid chromatography-tandem mass spectrometry analysis. The effect of iCCA-derived EVs as mediators of inflammation was assessed on monocytes by flow cytometry. iCCA-derived EVs showed downregulation of all SPL species. Of note, poorly-differentiated iCCA-derived EVs showed a higher ceramide and dihydroceramide content compared with moderately-differentiated iCCA-derived EVs. Of note, higher dihydroceramide content was associated with vascular invasion. Cancer-derived EVs induced the release of pro-inflammatory cytokines in monocytes. Inhibition of synthesis of ceramide with Myriocin, a specific inhibitor of the serine palmitoyl transferase, reduced the pro-inflammatory activity of iCCA-derived EVs, demonstrating a role for ceramide as mediator of inflammation in iCCA. In conclusion, iCCA-derived EVs may promote iCCA progression by exporting the excess of pro-apoptotic and pro-inflammatory ceramides.

Protein-Sparing Effect of α-Lipoic Acid in Diets with Different Protein/Carbohydrate Ratios for the Oriental River Prawn, Macrobrachium nipponense

Carbohydrates are commonly used in aquaculture feed because they are the cheapest energy source. Promoting carbohydrate catabolism for energy production can increase the dietary protein utilization efficiency (i.e., a protein-sparing effect). Alpha-lipoic acid (α-LA) is a cofactor of some rate-limiting key enzymes (pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase) in carbohydrate metabolism. To determine whether α-LA could promote carbohydrate catabolism to have a protein-sparing effect, we investigated the growth, activities of key enzymes involved in carbohydrate metabolism, transcript levels of genes encoding enzymes involved in energy metabolism, and the hepatopancreas structure of Macrobrachium nipponense fed with diets containing different protein/carbohydrate ratios (P/C) with and without α-LA. Six experimental diets for M. nipponense were formulated with casein and fish meal as the protein sources, fish oil and soybean oil as the lipid sources, and corn starch as the carbohydrate source. The six diets consisted of three different P/Cs ( P 41 / C 18 , P 37 / C 24 , and P 33 / C 30 ) without or with α-LA (at 1300 mg/kg). Each diet had six replicates and was fed to prawns (initial weight 0.110 ± 0.010 g) twice daily to apparent satiation. Dietary supplementation with α-LA significantly increased the survival rate of prawns, regardless of the P/C ratio. In the low-P/C group ( P 33 / C 30 ), the weight gain did not vary between those that consumed α-LA and those that did not. The P/C ratio and α-LA significantly affected the activities of key enzymes involved in glycolysis and the citric acid cycle. In the P 41 / C 18 group, the hexokinase (HK) and pyruvate dehydrogenase (PDH) activities were significantly higher in prawns that consumed α-LA than in those that did not. In both the P 37 / C 24 and P 33 / C 30 groups, the pyruvate kinase (PK) activity was significantly higher in prawns that consumed α-LA than in those that did not. Significant interactions between P/C and α-LA were found for the transcript levels of genes encoding adenine ribonucleotide-dependent protein kinase subunits (AMPK αand AMPK β), HK, glucose-6-phosphate dehydrogenase (G6PDH), acetyl-CoA carboxylase (ACC), and fatty acid binding protein 10 (FABP 10), all of which are involved in energy metabolism. In the low-P/C group, α-LA increased the transcript levels of genes encoding AMPK α, AMPK β, HK, phosphoenolpyruvate carboxykinase (PEPCK), G6PDH, and MDH, decreased the transcript level of the gene encoding ACC, and did not affect the transcript levels of genes encoding FABP10 and palmitoyl transferase 1 (CPT1). The P/C ratio and α-LA did not affect the overall morphology of the hepatopancreas, but at a low P/C, dietary supplementation of α-LA increased the number of hepatopancreatic B cells. In conclusion, supplementation with α-LA at 1300 mg/kg in a low-P/C diet of M. nipponense increased its carbohydrate utilization efficiency, energy metabolism, and the number of hepatopancreas B cells, thereby having a protein-sparing effect.

The combination of metformin with morin alleviates hepatic steatosis via modulating hepatic lipid metabolism, hepatic inflammation, brown adipose tissue thermogenesis, and white adipose tissue browning in high-fat diet-fed mice

AimThe valuable effects of metformin (MET) and morin (MOR) in the improvement of NAFLD have been proposed, nevertheless, their combination impacts were not investigated so far. We determined the therapeutic effects of combined MET and MOR treatment in high-fat diet (HFD)-induced Non-alcoholic fatty liver disease (NAFLD) mice. MethodsC57BL/6 mice were fed on an HFD for 15 weeks. Animals were allotted into various groups and supplemented with MET (230 mg/kg), MOR (100 mg/kg), and MET + MOR (230 mg/kg + 100 mg/kg). Key findingsMET in combination with MOR reduced body and liver weight in HFD-fed mice. A significant decrease in fasting blood glucose and improvement in glucose tolerance was observed in HFD mice treated with MET + MOR. Supplementation with MET + MOR led to a decline in hepatic triglyceride levels and this impact was associated with diminished expression of fatty-acid synthase (FAS) and elevated expression of carnitine palmitoyl transferase 1 (CPT1) and phospho-Acetyl-CoA Carboxylase (p-ACC). Moreover, MET combined with MOR alleviates hepatic inflammation through the polarization of macrophages to the M2 phenotype, decreasing the infiltration of macrophages and lowering the protein level of NF-kB. MET and MOR in combination reduce the size and weight of epididymal white adipose tissue (eWAT), and subcutaneous WAT (sWAT), whereas improves cold tolerance, BAT activity, and mitochondrial biogenesis. Combination therapy results in stimulating brown-like adipocyte (beige) formation in the sWAT of HFD mice. SignificanceThese results suggest that the combination of MET and MOR has a protective effect on hepatic steatosis, which may use as a candidate therapeutic for the improvement of NAFLD.

RETRACTED ARTICLE: Palmitoyl transferases act as novel drug targets for pancreatic cancer

BackgroundPancreatic adenocarcinoma (PAAD) is one of the most leading causes of cancer-related death across the world with the limited efficiency and response rate of immunotherapy. Protein S-palmitoylation, a powerful post-translational lipid modification, is well-known to regulate the stability and cellular distribution of cancer-related proteins, which is mediated by a family of 23 palmitoyl transferases, namely zinc finger Asp-His-His-Cys-type (ZDHHC). However, whether palmitoyl transferases can determine tumor progression and the efficacy of immunotherapy in PAAD remains unknown.MethodsBioinformatics methods were used to identify differential ZDHHCs expression in PAAD. A systematic pan-cancer analysis was conducted to assess the immunological role of ZDHHC3 using RNA sequencing data from The Cancer Genome Atlas database. In vivo Panc 02 subcutaneous tumor model validated the anti-tumor effect of knockdown of ZDHHC3 or intraperitoneal injection of 2-bromopalmitate (2-BP), a typical broad-spectrum palmitoyl transferases inhibitor. Furthermore, we explored therapeutic strategies with combinations of 2-BP with PD-1/PD-L1-targeted immunotherapy in C57BL/6 mice bearing syngeneic Panc 02 pancreatic tumors.ResultsZDHHC enzymes were associated with distinct prognostic values of pancreatic cancer. We identified that ZDHHC3 expression promotes an immunosuppressive tumor microenvironment in PAAD. 2-BP suppressed pancreatic-tumor cell viability and tumor sphere-forming activities, as well as increased cell apoptosis in vitro, without affecting normal human pancreatic ductal epithelial cells. Furthermore, genetic inactivation of ZDHHC3 or intraperitoneal injection of 2-BP impeded tumor progression in Panc 02 pancreatic tumors with enhanced anti-tumor immunity. 2-BP treatment significantly enhanced the therapeutic efficacy of PD-1/PD-L1 inhibitors in Panc 02 pancreatic tumors.ConclusionThis study revealed some ZDHHC enzyme genes for predicting the prognosis of pancreatic cancer, and demonstrated that ZDHHC3 plays a critical oncogenic role in pancreatic cancer progression, highlighting its potential as an immunotherapeutic target of pancreatic cancer. In addition, combination therapy of 2-BP and PD-1/PD-L1 achieved synergic therapy effects in a mouse model of pancreatic cancer.

Effects of Starvation and Refeeding on Growth, Digestion, Nonspecific Immunity and Lipid-Metabolism-Related Genes in Onychostoma macrolepis.

The present research was conducted to assess the influences of starvation and refeeding on growth, nonspecific immunity and lipid metabolic adaptation in Onychostoma macrolepis. To date, there have been no similar reports in O. macrolepis. The fish were randomly assigned into two groups: control group (continuous feeding for six weeks) and starved-refed group (starvation for three weeks and then refeeding for three weeks). After three weeks of starvation, the results showed that the body weight (BW, 1.44 g), condition factor (CF, 1.17%), visceral index (VSI, 3.96%), hepatopancreas index (HSI, 0.93%) and intraperitoneal fat index (IPFI, 0.70%) of fish were significantly lower compared to the control group (BW, 5.72 g; CF, 1.85%; VSI, 6.35%; HSI, 2.04%; IPFI, 1.92%) (p < 0.05). After starvation, the serum triglyceride (TG, 0.83 mmol/L), total cholesterol (T-GHOL, 1.15 mmol/L), high-density lipoprotein (HDL, 1.13 mmol/L) and low-density lipoprotein (LDL, 0.46 mmol/L) concentrations were significantly lower than those in the control group (TG, 1.69 mmol/L; T-GHOL, 1.86 mmol/L; HDL, 1.62 mmol/L; LDL, 0.63 mmol/L) (p < 0.05). The activities of intestinal digestive enzymes (amylase, lipase and protease) in the starved-refed group were significantly lower than those in the control group after three weeks of starvation (p < 0.05). The highest activities of immune enzymes such as lysozyme (LZM), acid phosphate (ACP), alkaline phosphate (ALP), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and catalase (CAT) in the hepatopancreas were presented in the starved-refed group at second week, and significantly higher than those in the control group (p < 0.05). Meanwhile, starvation significantly improved intestinal immune enzymes activities (p < 0.05). the lowest TG contents and the highest expression levels of lipolysis genes including hormone-sensitive lipase (HSL) and carnitine palmitoyl transferase 1 isoform A (CPT-1A) appeared in the hepatopancreas, muscle and intraperitoneal fat after starvation, indicating the mobilization of fat reserves in these tissues (p < 0.05). After refeeding, the recovery of TG content might be mediated by the upregulation of the expression levels of lipogenesis genes such as sterol regulatory element binding protein 1 (SREBP1) and fatty acid synthase (FAS). Understanding the duration of physiological and metabolic changes in O. macrolepis and their reversibility or irreversibility to supplementary feeding response could provide valuable reference for the adaptability of O. macrolepis in large-scale culturing, proliferation and release.

Atomoxetine and Fluoxetine Activate AMPK-ACC-CPT1 Pathway in Human SH-SY5Y and U-87 MG Cells.

Atomoxetine and fluoxetine are psychopharmacologic agents associated with loss of appetite and weight. Adenosine monophosphate-activated protein kinase (AMPK) is the cellular energy sensor that regulate metabolism and energy, being activated by fasting and inhibited by feeding in the hypothalamus. Human brain cell lines (SH-SY5Y and U-87 MG cells) were used to study the outcome of atomoxetine and fluoxetine treatment in the activity of AMPK-acetyl-CoA carboxylase (ACC)- carnitine palmitoyl transferase 1 (CPT1) pathway and upstream regulation by calcium/calmodulin-dependent kinase kinase β (CaMKKβ) using immunoblotting and CPT1 enzymatic activity measures. Phosphorylation of AMPK and ACC increased significantly after atomoxetine and fluoxetine treatment in the first 30-60 minutes of treatment in the two cell lines. Activation of AMPK and inhibition of ACC was associated with an increase by 5-fold of mitochondrial CPT1 activity. Although the neuronal isoform CPT1C could be detected by immunoblotting, activity was not changed by the drug treatments. In addition, the increase in phospho-AMPK and phospho-ACC expression induced by atomoxetine was abolished by treatment with STO-609, a CaMKKβ inhibitor, indicating that AMPK-ACC-CPT1 pathway is activated through CaMKKβ phosphorylation. These findings indicate that at the cellular level atomoxetine and fluoxetine treatments may activate AMPK-ACC-CPT1 pathways through CaMKKβ in human SH-SY5Y and U-87 MG cells.

Role of SUMO-Specific Protease 2 in Leptin-Induced Fatty Acid Metabolism in White Adipocytes.

Leptin is a 16-kDa fat-derived hormone with a primary role in controlling adipose tissue levels. Leptin increases fatty acid oxidation (FAO) acutely through adenosine monophosphate-activated protein kinase (AMPK) and on delay through the SUMO-specific protease 2 (SENP2)-peroxisome proliferator-activated receptor δ/γ (PPARδ/γ) pathway in skeletal muscle. Leptin also directly increases FAO and decreases lipogenesis in adipocytes; however, the mechanism behind these effects remains unknown. Here, we investigated the role of SENP2 in the regulation of fatty acid metabolism by leptin in adipocytes and white adipose tissues. The effects of leptin mediated by SENP2 on fatty acid metabolism were tested by siRNA-mediated knockdown in 3T3-L1 adipocytes. The role of SENP2 was confirmed in vivo using adipocyte-specific Senp2 knockout (Senp2-aKO) mice. We revealed the molecular mechanism involved in the leptin-induced transcriptional regulation of carnitine palmitoyl transferase 1b (Cpt1b) and long-chain acyl-coenzyme A synthetase 1 (Acsl1) using transfection/reporter assays and chromatin immunoprecipitation. SENP2 mediated the increased expression of FAO-associated enzymes, CPT1b and ACSL1, which peaked 24 hours after leptin treatment in adipocytes. In contrast, leptin stimulated FAO through AMPK during the initial several hours after treatment. In white adipose tissues, FAO and mRNA levels of Cpt1b and Acsl1 were increased by 2-fold 24 hours after leptin injection in control mice but not in Senp2-aKO mice. Leptin increased PPARα binding to the Cpt1b and Acsl1 promoters in adipocytes through SENP2. These results suggest that the SENP2-PPARα pathway plays an important role in leptin-induced FAO in white adipocytes.

Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer.

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

Black Rice Anthocyanidins Regulates Gut Microbiota and Alleviates Related Symptoms through PI3K/AKT Pathway in Type 2 Diabetic Rats

Black rice anthocyanins (BRAs) have extremely high nutritional value and health care effects. This study investigated the intervention effect of BRAs on type 2 diabetes mellitus (T2DM) and the regulation effect on intestinal microbiota imbalance in T2DM rats. This study established successfully a T2DM model in a high-fat and high-glucose diet combined with streptozotocin (STZ). BRAs intervention reduced significantly the fasting blood glucose level of T2DM rats, improved the glucose tolerance of rats, reduced the blood lipid level and inflammation state, and repaired liver, oxidative stress, and other injuries. In addition, BRAs’s intervention enhanced the expression of phosphoinositol 3-kinase (PI3K)/protein kinase B (AKT), activated the expression of adenosine 5’-monophosphate-activated protein kinase(AMPK), and the downstream acetyl-CoA carboxylase (ACC) and carnitine palmitoyl transferase (CPT1) in the liver. 16S rRNA sequencing showed that BRAs significantly decreased the abundances of Bifidobacterium and Clostridiaceae_Clostridium, and promoted the abundances of Akkermansia and Lactobacillus. Accelerate the recovery of gut microbiota diversity. BRAs play an antidiabetic role by regulating the PI3K/AKT signaling pathway and intestinal microbiota in T2MD rats.

CD4+ T cells expressing CX3CR1, GPR56, with variable CD57 are associated with cardiometabolic diseases in persons with HIV.

Persons with HIV (PWH) on long-term antiretroviral therapy (ART) have a higher incidence and prevalence of cardiometabolic diseases attributed, in part, to persistent inflammation despite viral suppression. In addition to traditional risk factors, immune responses to co-infections such as cytomegalovirus (CMV) may play an unappreciated role in cardiometabolic comorbidities and offer new potential therapeutic targets in a subgroup of individuals. We assessed the relationship of CX3CR1+, GPR56+, and CD57+/- T cells (termed CGC+) with comorbid conditions in a cohort of 134 PWH co-infected with CMV on long-term ART. We found that PWH with cardiometabolic diseases (non-alcoholic fatty liver disease, calcified coronary arteries, or diabetes) had higher circulating CGC+CD4+ T cells compared to metabolically healthy PWH. The traditional risk factor most correlated with CGC+CD4+ T cell frequency was fasting blood glucose, as well as starch/sucrose metabolites. While unstimulated CGC+CD4+ T cells, like other memory T cells, depend on oxidative phosphorylation for energy, they exhibited higher expression of carnitine palmitoyl transferase 1A compared to other CD4+ T cell subsets, suggesting a potentially greater capacity for fatty acid β-oxidation. Lastly, we show that CMV-specific T cells against multiple viral epitopes are predominantly CGC+. Together, this study suggests that among PWH, CGC+ CD4+ T cells are frequently CMV-specific and are associated with diabetes, coronary arterial calcium, and non-alcoholic fatty liver disease. Future studies should assess whether anti-CMV therapies could reduce cardiometabolic disease risk in some individuals.

Food Deprivation Modifies Fatty Acid Partitioning and β-Oxidation Capacity in Rat Liver

The involvement of lipids under starvation conditions in the shift from the phase of protein sparing (phase II) to the phase of increased protein breakdown (phase III) has been investigated. Plasma and liver were sampled from fed and unfed rats at two distinct stages which were characterized according to the changes in specific loss in daily body mass and nitrogen excretion. In the two groups of food-deprived rats corresponding to phases II and III, the liver concentration of triglycerides (µmol/g) was significantly lower, that of cholesterol significantly higher and that of the other lipid classes was moderately affected compared with concentrations in fed rats. Hepatic phospholipids had significantly higher concentrations (mol/100 mol) of 22:6(n-3) in food-deprived rats than in fed rats. Triglycerides had significantly higher concentrations of stearic and arachidonic acids in livers of both groups of food-deprived rats compared with fed rats. The total activity of carnitine palmitoyl transferase [mmol/(min·liver)] was 48% higher in rats studied at the end of phase II than in fed rats but was similar in fed rats and in rats studied at the beginning of phase III. The total activity of fatty acyl-CoA oxidase was 73% lower only in rats studied at the beginning of phase III when compared with fed rats. Our results indicate that during food deprivation the change in the rate of protein utilization is associated with important qualitative and quantitative alterations of hepatic lipids and oxidative capacity of fatty acids. These modifications appear to be related to the change from a preferential use of lipids to a preferential utilization of proteins.

Abstract TMP29: Elevated Levels Of Palmitic Acid Mediate Early Disruption Of Endothelial Barrier Integrity And Promote Behavioral Dysfunction Relevance To Vascular Cognitive Impairment And Dementia (VCID)

Increased consumption of a high-fat diet (HFD) is believed to increase the risk for the development and progression of VCID, but the underlying mechanisms of how HFD leads to cognitive impairment are unclear, partly due to the use of different HFD models in preclinical studies. Palmitic acid (PA), the most common form of saturated fatty acid, found in the human cerebrospinal fluid in obesity, promotes disruption of BBB integrity. We hypothesized that a PA-rich diet mediates early disruption of blood brain barrier (BBB) integrity which leads to progressive neurovascular pathologies and cognitive impairment in VCID. Methods: Experimental design for in vivo studies is depicted in Fig 1. In vitro studies included assessment of endothelial integrity by trans-endothelial electrical resistance (TEER) and FITC measurements, cell viability, and expression levels of tight junction proteins and cell stress markers (Hsp70, Occludin1, Claudin 5, and Carnitine Palmitoyl transferase 1A -CTP1A) in male BMVECs cultured in normal and high PA conditions. Results (Table): Animals that were on the PA-rich diet exhibited risk-taking behavior. BMVECs showed significantly increased permeability of FITC-dextran and decreased TEER measurements. While Hsp70 and CTP1A increased with PA treatment, tight junction protein levels did not change. Conclusion: A special PA-rich diet mediates an anxiety-like behavior as early as 8 weeks without any metabolic effects. Assessments at 22 and 24W will determine whether behavioral dysfunction worsens and progresses to cognitive deficits. In vitro results suggest that initiation of the stress response may be the underlying mechanism of early BBB impairment. Modulation of the endothelial stress response may prevent/attenuate the development/progression of cognitive deficits induced by a PA-rich diet.

L-carnitine attenuated hyperuricemia-associated left ventricular remodeling through ameliorating cardiomyocytic lipid deposition.

Hyperuricemia (HUA) is associated with left ventricular remodeling (LVR) and thereby causes the initiation and development of a large number of cardiovascular diseases. LVR is typically accompanied by cardiomyocyte energy metabolic disorder. The energy supply of cardiomyocytes is provided by glucose and fatty acid (FA) metabolism. Currently, the effect of HUA on cardiomyocytic FA metabolism is unclear. In this study, we demonstrate that UA-induced cardiomyocyte injury is associated with cytoplasmic lipid deposition, which can be ameliorated by the FA metabolism-promoting drug L-carnitine (LC). UA suppresses carnitine palmitoyl transferase 1B (CPT1B), thereby inhibiting FA transport into the mitochondrial inner matrix for elimination. LC intervention can ameliorate HUA-associated left ventricular anterior wall thickening in mice. This study showed that FA transport dysfunction plays is a critical mechanism in both cardiomyocytic injury and HUA-associated LVR and promoting cytoplasmic FA transportation through pharmacological treatment by LC is a valid strategy to attenuate HUA-associated LVR.

Long-Term Dietary Supplementation with Betaine Improves Growth Performance, Meat Quality and Intramuscular Fat Deposition in Growing-Finishing Pigs.

This study was designed to investigate the effects of dietary betaine supplementation on growth performance, meat quality and muscle lipid metabolism of growing-finishing pigs. Thirty-six crossbred pigs weighing 24.68 ± 0.97 kg were randomly allotted into two treatments consisting of a basal diet supplemented with 0 or 1200 mg/kg betaine. Each treatment included six replications of three pigs per pen. Following 119 days of feeding trial, dietary betaine supplementation significantly enhanced average daily gain (ADG) (p < 0.05) and tended to improve average daily feed intake (ADFI) (p = 0.08) and decreased the feed intake to gain ratio (F/G) (p = 0.09) in pigs during 100~125 kg. Furthermore, a tendency to increase ADG (p = 0.09) and finial body weight (p = 0.09) of pigs over the whole period was observed in the betaine diet group. Betaine supplementation significantly increased a*45 min and marbling and decreased b*24 h and cooking loss in longissimus lumborum (p < 0.05), tended to increase intramuscular fat (IMF) content (p = 0.08), however had no significant influence on carcass characteristics (p > 0.05). Betaine supplementation influenced the lipid metabolism of pigs, evidenced by a lower serum concentration of low-density lipoprotein cholesterol (p < 0.05), an up-regulation of mRNA abundance of fatty acid synthase and acetyl-CoA carboxylase (p < 0.05), and a down-regulation of mRNA abundance of lipolysis-related genes, including the silent information regulators of transcription 1 (p = 0.08), peroxisome proliferator-activated receptorα (p < 0.05), peroxisome proliferator-activated receptor gamma coactivator-1α (p = 0.07) and carnitine palmitoyl transferase 1 (p < 0.05) in longissimus lumborum. Moreover, betaine markedly improved the expression of microRNA-181a (miR-181a) (p < 0.05) and tended to enhance miR-370 (p = 0.08). Overall, betaine supplementation at 1200 mg/kg could increase the growth performance of growing-finishing pigs. Furthermore, betaine had a trend to improve meat quality and IMF content via increasing lipogenesis and down-regulating the abundance of genes associated with lipolysis, respectively, which was associated with the regulation of miR-181a and miR-370 expression by betaine.

Effect of dietary concentrations of metabolizable energy and neutral detergent fiber on productive performance, egg quality, fatty liver incidence, and hepatic fatty acid metabolism in aged laying hens

The objective of the current experiment was to investigate the effect of dietary concentrations of ME and neutral detergent fiber (NDF) on productive performance, egg quality, fatty liver incidence, and hepatic fatty acid metabolism in aged laying hens. A total of three hundred twenty 75-wk-old Hy-Line Brown laying hens were allotted to 1 of 4 dietary treatments with 8 replicates. Each replicate consisted of 10 consecutive cages with 1 hen per cage. The experiment was conducted using a completely randomized design with 2×2 factorial arrangement consisting of 2 levels of ME (normal [commercially recommended AMEn levels; 2,730 kcal/kg] and low [50 kcal/kg reduction in AMEn; 2,680 kcal/kg]) and 2 levels of NDF (low [9.01 and 9.61%; normal-ME and low-ME diets, respectively] and high [12.57 and 13.42%; normal-ME and low-ME diets, respectively]) in the diet. The diets and water were provided to hens on an ad libitum basis for 12 wk. Results indicated that no interactions between dietary concentrations of ME and NDF were observed for all measurements except for egg yolk color, eggshell thickness, and 2 hepatic gene expressions (i.e., carnitine palmitoyl transferase 1A and malic enzyme). For the main effects, increasing NDF concentrations in diets increased (P < 0.05) feed intake without affecting other productive performance. Hens fed normal-ME and high-NDF diets showed the darkest (P < 0.05) egg yolk color among those fed treatment diets, showing an interaction (P < 0.05). Increasing NDF concentrations in low-ME diets did not influence eggshell thickness, but those in normal-ME diets increased eggshell thickness in laying hens, showing an interaction (P < 0.05). For the main effects, increasing concentrations of dietary NDF or ME reduced (P < 0.05) hepatic fat concentrations with decreasing expressions in several genes related to fatty acid synthesis. In conclusion, increasing NDF concentrations in commercially-recommended ME diets decrease hepatic fat concentrations in aged laying hens, and therefore, may have a preventative effect on the fatty liver development in aged laying hens.

Effects of peroxisome proliferator activated receptor-α agonist on growth performance, blood profiles, gene expression related to liver fat metabolism in broilers fed diets containing corn naturally contaminated with mycotoxins.

This study was conducted to determine the subclinical symptom of broilers exposure to mycotxoins from corn naturally contaminated, and the preventive effect with peroxisome proliferator activated receptor-α (PPARα) agonist (Wy-14643) supplementation. A total of 360 one-day -old male Arbor Acres broilers were randomly distributed into 4 treatments with 9 replicates of 10 birds. Dietary treatments included: treatment 1, normal corn diets group, treatment 2, normal corn + Wy-14643 diets group, treatment 3, mycotoxin-contaminated corn diets group, treatment 4, mycotoxin-contaminated corn + Wy-14643 diets group. The supplementation of Wy-14643 was added at the expense of 1 and 2 mg/kg in starter and grower diets, respectively. Birds fed mycotoxin diets had lower (P < 0.05) final body weight (BW), Body weight gain (BWG), feed intake (FI), and had higher (P < 0.05) feed conversion ratio (FCR). Feeding mycotoxin diets reduced (P < 0.05) the levels of serum superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), catalase (CAT), total antioxidative capacity (T-AOC) and high-density lipoprotein cholesterol (HDL-C), but higher malondialdehyde (MDA), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and fatty acid synthetase (FAS). The supplementation of Wy-14643 increased (P < 0.05) the level of serum T-AOC, but reduced (P < 0.05) TG and LDL-C. Interactive effect was not observed (P > 0.05) in growth performance and blood profiles. The relative expression of PPARα mRNA and 3-Hydroxy-3-MethylGlutaryl-CO enzyme A (HMGCoA) mRNA was higher (P < 0.05) in treatment 3 and treatment 4 than treatment 1 and treatment 2, and there was significant difference (P <0.05) between treatment 3 and treatment 4. There was significant difference (P < 0.05) between groups of the relative expression of recombinant carnitine palmitoyl transferase 1 (CPT1) mRNA. The relative expression of acyl CoA oxidase (ACO) mRNA was higher (P < 0.05) in treatment 1 and treatment 4 than treatment 2 and treatment 3, and there was significant difference (P < 0.05) between treatment 1 and treatment 4. The relative expression of apolipoprotein A (APO-A) mRNA was higher (P < 0.05) in treatment 1 and treatment 4 than treatment 2 and treatment 3. The relative expression of sterol regulatory element binding protein (SREBP) mRNA was lower (P < 0.05) in treatment 2, treatment 3 and treatment 4 than treatment 1, and there was significant difference (P < 0.05) between treatment 3 and treatment 4. Overall, feeding naturally contaminated mycotoxin diets caused negative effects on growth performance and blood profiles, while diet supplementation with Wy-14643 alleviate the detrimental effects on gene and expression related to liver fat metabolism in broilers.