Lipid Secretion Research Articles

Xanthine oxidoreductase mediates membrane docking of milk-fat droplets but is not essential for apocrine lipid secretion.

Xanthine oxidoreductase (XOR) modulates milk lipid secretion and lactation initiation. XOR is required for butyrophilin1a1 clustering in the membrane during milk lipid secretion. XOR mediates apical membrane reorganization during milk lipid secretion. Loss of XOR delays milk fat globule secretion. XOR loss alters the proteome of milk fat globules. Apocrine secretion is utilized by epithelial cells of exocrine glands. These cells bud off membrane-bound particles into the lumen of the gland, losing a portion of the cytoplasm in the secretion product. The lactating mammary gland secretes milk lipid by this mechanism, and xanthine oxidoreductase (XOR) has long been thought to be functionally important. We generated mammary-specific XOR knockout (MGKO) mice, expecting lactation to fail. Histology of the knockout glands showed very large lipid droplets enclosed in the mammary alveolar cells, but milk analysis showed that these large globules were secreted. Butyrophilin, a membrane protein known to bind to XOR, was clustered at the point of contact of the cytoplasmic lipid droplet with the apical plasma membrane, in the wild-type gland but not in the knockout, suggesting that XOR mediates 'docking' to this membrane. Secreted milk fat globules were isolated from mouse milk of wild-type and XOR MGKO dams, and subjected to LC-MS/MS for analysis of protein component. Proteomic results showed that loss of XOR leads to an increase in cytoplasmic, cytoskeletal, Golgi apparatus and lipid metabolism proteins associated with the secreted milk fat globule. Association of XOR with the lipid droplet results in membrane docking and more efficient retention of cytoplasmic components by the secretory cell. Loss of XOR then results in a reversion to a more rudimentary, less efficient, apocrine secretion mechanism, but does not prevent milk fat globule secretion.

Effects of exercise training on intrahepatic lipid content in humans.

Non-alcoholic fatty liver (NAFL) is the most common liver disorder in western society. Various factors may play a role in determining hepatic fat content, such as delivery of lipids to the liver, de novo lipogenesis, hepatic lipid oxidation, secretion of intrahepatic lipids to the circulation or a combination of these. If delivery of lipids to the liver outweighs the sum of hepatic lipid oxidation and secretion, the intrahepatic lipid (IHL) content starts to increase and NAFL may develop. NAFL is closely related to obesity and insulin resistance and a fatty liver increases the vulnerability to type 2 diabetes development. Exercise training is a cornerstone in the treatment and prevention of type 2 diabetes. There is a large body of literature describing the beneficial metabolic consequences of exercise training on skeletal muscle metabolism. Recent studies have started to investigate the effects of exercise training on liver metabolism but data is still limited. Here, first, we briefly discuss the routes by which IHL content is modulated. Second, we review whether and how these contributing routes might be modulated by long-term exercise training. Third, we focus on the effects of acute exercise on IHL metabolism, since exercise also might affect hepatic metabolism in the physically active state. This will give insight into whether the effect of exercise training on IHL could be explained by the accumulated effect of acute bouts of exercise, or whether adaptations might occur only after long-term exercise training. The primary focus of this review will be on observations made in humans. Where human data is missing, data obtained from well-accepted animal models will be used.

Lipid metabolism and production of incretins in patients with obesity and type 2 diabetes mellitus after biliopancreatic diversion in Hess-Marceau modification at the early stages of follow-up

Objectives: To study the lipid metabolism and secretion of GLP-1 and GIP in obese patients with type 2 diabetes before and 3 months after biliopancreatic diversion (BPD) in Hess-Marceau modification.Materials and methods: 22 patients (44 [38.0; 55.0] years) with morbid obesity (BMI of 50.1 [41.3; 53.8]) and type 2 diabetes were included in the study. Total cholesterol, LDL-C, HDL-C, TG, GLP-1, GIP were evaluated before and 3 months after BPD.Results: At 3 months after BPD there were decreases in weight by 15.8% and a reduction in total cholesterol levels and LDL-C, an increase in the number of patients with a target value of total cholesterol and LDL-C (from 4/22 (18%) to 20/22 (91%, p = 0.0001)). TG levels during the first 3 months after BPD did not change, but there was a trend to an increase in the number of patients with TG target levels (from 8/22 (32%) to 15/22 (68%, p = 0.058)). Due to the reduction of total cholesterol intake after malabsorbtive surgery, we saw a regular decrease in HDL-cholesterol. 3 months after BPD there was an increase in basal secretion of GLP-1 and GIP as compared to preoperative levels, and a strong positive association of the basal GIP with the HDL-C (r = 0,8, p = 0.007) and a strong negative association – with the atherogenic index (r = – 0,7, p = 0.009) at 3 weeks after surgery.Conclusions: The majority of patients with obesity and type 2 diabetes as early as at 3 months after BPD in the modification by Hess-Marceau achieve a significant improvement in the parameters of lipid metabolism; expect positive impact of the GIP on lipid metabolism.

Effects of activation of endocannabinoid system on myocardial metabolism.

Endocannabinoids exert their effect on the regulation of energy homeostasis via activation of specific receptors. They control food intake, secretion of insulin, lipids and glucose metabolism, lipid storage. Long chain fatty acids are the main myocardial energy substrate. However, the heart exerts enormous metabolic flexibility emphasized by its ability to utilzation not only fatty acids, but also glucose, lactate and ketone bodies. Endocannabinoids can directly act on the cardiomyocytes through the CB1 and CB2 receptors present in cardiomyocytes. It appears that direct activation of CB1 receptors promotes increased lipogenesis, pericardial steatosis and bioelectrical dysfunction of the heart. In contrast, stimulation of CB2 receptors exhibits cardioprotective properties, helping to maintain appropriate amount of ATP in cardiomyocytes. Furthermore, the effects of endocannabinoids at both the central nervous system and peripheral tissues, such as liver, pancreas, or adipose tissue, resulting indirectly in plasma availability of energy substrates and affects myocardial metabolism. To date, there is little evidence that describes effects of activation of the endocannabinoid system in the cardiovascular system under physiological conditions. In the present paper the impact of metabolic diseases, i. e. obesity and diabetes, as well as the cardiovascular diseases - hypertension, myocardial ischemia and myocardial infarction on the deregulation of the endocannabinoid system and its effect on the metabolism are described.

MicroRNA-186 promotes macrophage lipid accumulation and secretion of pro-inflammatory cytokines by targeting cystathionine γ-lyase in THP-1 macrophages

Background and aimsSeveral studies suggest that cardiomyocyte-enriched miR-186 is involved in cardiac injury and myocardial infarction, and also plays an important role in atherosclerotic diseases, but the underlying mechanism is unknown. Cystathionine-γ-lyase (CSE) is the predominant enzyme to produce H2S in the cardiovascular system. Here, miR-186 was identified to bind to the 3′UTR of CSE. In this study, we aimed at exploring whether miR-186 affects lipid accumulation and secretion of pro-inflammatory cytokines by targeting CSE and its underlying mechanism in human THP-1 macrophages and peripheral blood monocyte-derived macrophages (PBMDM). PBMDM just as a control group for the comparison with the THP-1 macrophages. MethodsMiR-186 target genes, CSE 3′UTR sequence and free energy were predicted and analyzed by bioinformatics analyses and dual-luciferase reporter assays. The expression of CSE mRNA and protein were measured by real-time quantitative PCR and western blot analyses. The lipid accumulation in THP-1 macrophages was detected by high performance liquid chromatography (HPLC). The effects of miR-186 on secretion of IL-6, IL-1β and TNF-α were examined by ELISA. Endogenous H2S was detected by spectrophotometry. Using small interfering RNA (siRNA) approach to decrease the expression of CSE protein and mRNA. ResultsWe found that miR-186 directly inhibited CSE protein and mRNA expression through targeting CSE 3′UTR by bioinformatics analyses and dual-luciferase reporter assays. HPLC assays showed that miR-186 increased the lipid accumulation in human THP-1 macrophages. We also showed that miR-186 enhanced secretion of pro-inflammatory cytokines in human THP-1 macrophages. Using siRNA approach, we found that CSE siRNA could inhibit the miR-186 inhibitor-induced decrease in the expression of LPL protein and mRNA in human THP-1 macrophages, which was accompanied a decrease in the level of H2S. ConclusionsMicroRNA-186 promotes macrophage lipid accumulation and pro-inflammatory cytokine secretion by targeting cystathionine γ-lyase in THP-1 macrophages.

Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis.

Drug-induced liver injury is an important clinical entity resulting in a considerable number of hospitalizations. While drug-induced cholestasis due to the inhibition of the bile salt export pump (BSEP) is well investigated, only limited information on the interaction of drugs with multidrug resistance protein 3 (MDR3) exists and its role in the pathogenesis of drug-induced cholestasis is poorly understood. Therefore, we aimed to study the interaction of drugs with MDR3 and the effect of drugs on canalicular lipid secretion in a newly established polarized cell line system that serves as a model of canalicular lipid secretion. LLC-PK1 cells were stably transfected with human Na(+)-taurocholate cotransporting polypeptide, BSEP, MDR3, and ABCG5/G8 and grown in the Transwell system. Apical phospholipid secretion and taurocholate transport were assayed to investigate the effect of selected drugs on MDR3-mediated phospholipid secretion as well as inhibition of BSEP. The established cell line displayed vectorial bile salt transport and specific phosphatidylcholine secretion into the apical compartment. The antifungal azoles, posaconazole, itraconazole, and ketoconazole, significantly inhibited MDR3-mediated phosphatidylcholine secretion. In contrast, amoxicillin clavulanate and troglitazone did not interfere with MDR3 activity. Drugs interfering with MDR3 activity did not display a parallel inhibition of BSEP. Our in vitro model for MDR3-mediated phospholipid secretion facilitates parallel screening for MDR3 and BSEP inhibitors. Our data demonstrate that the cholestatic potential of certain drugs may be aggravated by simultaneous inhibition of BSEP and MDR3.

Bacillus Subtilis-Fermented Red Bean (Red Bean Natto) Reduces Hyperlipidemia Levels in Hamsters Fed an Atherogenic Diet

The purpose of this study was to investigate the effects of 50% red beans ethanol natto extracts fermented by Bacillus subtilis on hyperlipidemia in hamsters. Forty male hamsters were randomly assigned to normal control, high-fat control, and high-fat with RBNE (red beans natto extracts) (200 and 1000 mg/kg BW) groups. RBNE treatment for 8 weeks significantly decreased the body and visceral fat weight in hamsters. Compared to the high-fat diet group, the plasma total cholesterol (TC), total triacylglycerol (TAG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and oxidized LDL (oxLDL) concentrations as well as atherogenic index of plasma AIP [Log(TAG/HDL-C)] were significantly lower in the RBNE-fed group. The consumption of RBNE significantly reduced the liver contents of TC, esterified cholesterol (CE) and alanine aminotransferase (ALT), and increased a regulator of lipid metabolism: peroxisome proliferator-activated receptor alpha (PPAR-alpha). Furthermore, the circulating level of irisin was decreased. Practical Application The oral administration of Bacillus subtilis-fermented red bean natto extract (RBNE), a popular Asian dessert, effectively moderated the metabolism of lipids and positively affected the blood and liver profiles of hamsters fed with a high-cholesterol and high-fat diet. Importantly, RBNE significantly suppressed the increase in visceral fat mass. Additionally, RBNE appears to protect the liver and alleviate the magnitude of fatty liver development. RBNE also upregulated PPAR-alpha protein expression in the liver, suggesting that supplementation may improve lipid metabolism in part through the beta-oxidation of lipids and promotion of lipid secretion. Furthermore, RBNE may ameliorate hyperlipidemia involving irisin, a newly identified hormone, in hamsters fed a cholesterol- and lipid-enriched diet. In conclusion, RBNE with high hypocholesterolemic activities may be helpful for patients with atherosclerosis.

Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis

Low-density lipoprotein receptor-related protein-1 (LRP1) is a multifunctional uptake receptor for chylomicron remnants in the liver. In vascular smooth muscle cells LRP1 controls reverse cholesterol transport through platelet-derived growth factor receptor β (PDGFR-β) trafficking and tyrosine kinase activity. Here we show that LRP1 regulates hepatic energy homeostasis by integrating insulin signaling with lipid uptake and secretion. Somatic inactivation of LRP1 in the liver (hLRP1KO) predisposes to diet-induced insulin resistance with dyslipidemia and non-alcoholic hepatic steatosis. On a high-fat diet, hLRP1KO mice develop a severe Metabolic Syndrome secondary to hepatic insulin resistance, reduced expression of insulin receptors on the hepatocyte surface and decreased glucose transporter 2 (GLUT2) translocation. While LRP1 is also required for efficient cell surface insulin receptor expression in the absence of exogenous lipids, this latent state of insulin resistance is unmasked by exposure to fatty acids. This further impairs insulin receptor trafficking and results in increased hepatic lipogenesis, impaired fatty acid oxidation and reduced very low density lipoprotein (VLDL) triglyceride secretion.

Short communication: Altered expression of specificity protein 1 impairs milk fat synthesis in goat mammary epithelial cells

Specificity protein 1 (encoded by SP1) is a novel transcription factor important for the regulation of lipid metabolism and the normal function of various hormones in model organisms. Its potential role, if any, on ruminant milk fat is unknown. Despite the lower expression of the lipolysis-related gene ATGL (by 44 and 37% respectively), both the adenoviral overexpression and the silencing of SP1 [via short interfering (si)RNA] markedly reduced cellular triacylglycerol (TAG) content (by 28 and 25%, respectively), at least in part by decreasing the expression of DGAT1 (−36% in adenovirus treatment) and DGAT2 (−81 and −87%, respectively) that are involved in TAG synthesis. Consistent with the markedly lower expression of genes related to lipid droplet formation and secretion (TIP47 by 19 and 32%, and ADFP by 25 and 25%, respectively), cellular lipid droplet content was also decreased sharply, by 9 and 8.5%, respectively, after adenoviral overexpression of SP1 or its silencing via siRNA. Overall, the results underscored a potentially important role of SP1 in maintaining milk-fat droplet synthesis in goat mammary epithelial cells.

How did nature engineer the highest surface lipid accumulation among plants? Exceptional expression of acyl-lipid-associated genes for the assembly of extracellular triacylglycerol by Bayberry (Myrica pensylvanica) fruits

Bayberry (Myrica pensylvanica) fruits are covered with a remarkably thick layer of crystalline wax consisting of triacylglycerol (TAG) and diacylglycerol (DAG) esterified exclusively with saturated fatty acids. As the only plant known to accumulate soluble glycerolipids as a major component of surface waxes, Bayberry represents a novel system to investigate neutral lipid biosynthesis and lipid secretion by vegetative plant cells. The assembly of Bayberry wax is distinct from conventional TAG and other surface waxes, and instead proceeds through a pathway related to cutin synthesis (Simpson and Ohlrogge, 2016). In this study, microscopic examination revealed that the fruit tissue that produces and secretes wax (Bayberry knobs) is fully developed before wax accumulates and that wax is secreted to the surface without cell disruption. Comparison of transcript expression to genetically related tissues (Bayberry leaves, M. rubra fruits), cutin-rich tomato and cherry fruit epidermis, and to oil-rich mesocarp and seeds, revealed exceptionally high expression of 13 transcripts for acyl-lipid metabolism together with down-regulation of fatty acid oxidases and desaturases. The predicted protein sequences of the most highly expressed lipid-related enzyme-encoding transcripts in Bayberry knobs are 100% identical to the sequences from Bayberry leaves, which do not produce surface DAG or TAG. Together, these results indicate that TAG biosynthesis and secretion in Bayberry is achieved by both up and down-regulation of a small subset of genes related to the biosynthesis of cutin and saturated fatty acids, and also implies that modifications in gene expression, rather than evolution of new gene functions, was the major mechanism by which Bayberry evolved its specialized lipid metabolism. This article is part of a Special Issue entitled: Plant Lipid Biology edited by Kent D. Chapman and Ivo Feussner.

Potential antihyperglycaemic effect of myricetin derivatives from Syzygium malaccense

Myricitrin, a flavonoid-3-O-glycoside, found present in many plant parts is reported to have the potential to serve as a functional food ingredient. In the present study, myricetin derivatives (F2) isolated from leaf extract of Syzygium malaccense, consisted of predominantly myricitrin (77%), were evaluated for in vitro anti-hyperglycaemic activity. The ability of the samples to inhibit carbohydrate hydrolyzing enzymes, stimulate adipogenesis, glucose uptake, adiponectin secretion and affect gene expression in differentiated 3T3-L1 pre-adipocytes was assessed. F2 significantly inhibited both α-glucosidase and α-amylase. It exhibited ‘insulin-like’ effects by enhancing accumulation of lipid, glucose uptake and adiponectin secretion by activating insulin signalling pathway similar to insulin. It upregulated Akt1 (protein kinase B), PPARγ (peroxisome proliferator activated receptor gamma) and Slc2a4 (glucose transporter) genes in addition to PRKAG2 (protein kinase, AMP activated) and adiponectin to stimulate glucose uptake. The above findings suggest that the myricetin derivatives may serve as functional food ingredient.

Ethanol and fatty acids impair lipid homeostasis in an in vitro model of hepatic steatosis

Excess ethanol consumption and fatty acid intake lead to a cumulative effect on liver steatosis through still unclear mechanisms. This study aimed to characterize the lipid homoeostasis alterations under the exposure of hepatocytes to ethanol alone or combined with fatty acids. FaO hepatoma cells were incubated in the absence (C) or in the presence of 100 mM ethanol (EtOH) or 0.35 mM oleate/palmitate (FFA) alone or in the combination (FFA/EtOH). Content of intra- and extra-cellular triglycerides (TAGs) and of lipid droplets (LDs), expression of lipogenic and lipolytic genes, and oxidative stress-related parameters were evaluated. Exposure to either FFAs or EtOH given separately led to steatosis which was augmented when they were combined. Our results show that FFA/EtOH: (i) increased the LD number, but reduced their size compared to separate treatments; (ii) up-regulated PPARγ and SREBP-1c and down-regulated sirtuin-1 (SIRT1); (iii) impaired FFA oxidation; (iv) did not change lipid secretion and oxidative stress. Our findings indicate that one of the major mechanisms of the metabolic interference between ethanol and fat excess is the impairment of FFA oxidation, in addition to lipogenic pathway stimulation. Interestingly, ethanol combined with FFAs led to a shift from macrovesicular to microvesicular steatosis that represents a more dangerous condition.

Mycobacterium tuberculosis WhiB3 Responds to Vacuolar pH-induced Changes in Mycothiol Redox Potential to Modulate Phagosomal Maturation and Virulence

The ability of Mycobacterium tuberculosis to resist intraphagosomal stresses, such as oxygen radicals and low pH, is critical for its persistence. Here, we show that a cytoplasmic redox sensor, WhiB3, and the major M. tuberculosis thiol, mycothiol (MSH), are required to resist acidic stress during infection. WhiB3 regulates the expression of genes involved in lipid anabolism, secretion, and redox metabolism, in response to acidic pH. Furthermore, inactivation of the MSH pathway subverted the expression of whiB3 along with other pH-specific genes in M. tuberculosis. Using a genetic biosensor of mycothiol redox potential (EMSH), we demonstrated that a modest decrease in phagosomal pH is sufficient to generate redox heterogeneity in EMSH of the M. tuberculosis population in a WhiB3-dependent manner. Data indicate that M. tuberculosis needs low pH as a signal to alter cytoplasmic EMSH, which activates WhiB3-mediated gene expression and acid resistance. Importantly, WhiB3 regulates intraphagosomal pH by down-regulating the expression of innate immune genes and blocking phagosomal maturation. We show that this block in phagosomal maturation is in part due to WhiB3-dependent production of polyketide lipids. Consistent with these observations, MtbΔwhiB3 displayed intramacrophage survival defect, which can be rescued bypharmacological inhibition of phagosomal acidification. Last, MtbΔwhiB3 displayed marked attenuation in the lungs of guinea pigs. Altogether, our study revealed an intimate link between vacuolar acidification, redox physiology, and virulence in M. tuberculosis and discovered WhiB3 as crucial mediator of phagosomal maturation arrest and acid resistance in M. tuberculosis.

Triglyceride Mobilization from Lipid Droplets Sustains the Anti-Steatotic Action of Iodothyronines in Cultured Rat Hepatocytes.

Adipose tissue, dietary lipids and de novo lipogenesis are sources of hepatic free fatty acids (FFAs) that are stored in lipid droplets (LDs) as triacylglycerols (TAGs). Destiny of TAGs stored in LDs is determined by LD proteomic equipment. When adipose triglyceride lipase (ATGL) localizes at LD surface the lipid mobilization is stimulated. In this work, an in vitro model of cultured rat hepatocytes mimicking a mild steatosis condition was used to investigate the direct lipid-lowering action of iodothyronines, by focusing, in particular, on LD-associated proteins, FFA oxidation and lipid secretion. Our results demonstrate that in “steatotic” hepatocytes iodothyronines reduced the lipid excess through the recruitment of ATGL on LD surface, and the modulation of the LD-associated proteins Rab18 and TIP47. As an effect of ATGL recruitment, iodothyronines stimulated the lipid mobilization from LDs then followed by the up-regulation of carnitine-palmitoyl-transferase (CPT1) expression and the stimulation of cytochrome-c oxidase (COX) activity that seems to indicate a stimulation of mitochondrial function. The lipid lowering action of iodothyronines did not depend on increased TAG secretion. On the basis of our data, ATGL could be indicated as an early mediator of the lipid-lowering action of iodothyronines able to channel hydrolyzed FFAs toward mitochondrial beta-oxidation rather than secretion.

The cholecystokinin-1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice.

A defect in gallbladder contraction function plays a key role in the pathogenesis of gallstones. The cholecystokinin-1 receptor (CCK-1R) antagonists have been extensively investigated for their therapeutic effects on gastrointestinal and metabolic diseases in animal studies and clinical trials. However, it is still unknown whether they have a potential effect on gallstone formation. To study whether the CCK-1R antagonists enhance cholelithogenesis, we investigated cholesterol crystallization, gallstone formation, hepatic lipid secretion, gallbladder emptying function and intestinal cholesterol absorption in male C57BL/6J mice treated by gavage with devazepide (4 mg/day/kg) or vehicle (as controls) twice per day and fed the lithogenic diet for 21 days. During 21 days of feeding, oral administration of devazepide significantly accelerated cholesterol crystallization and crystal growth to microlithiasis, with 40% of mice forming gallstones, whereas only agglomerated cholesterol monohydrate crystals were found in mice receiving vehicle. Compared to the vehicle group, fasting and postprandial residual gallbladder volumes in response to the high-fat meal were significantly larger in the devazepide group during cholelithogenesis, showing reduced gallbladder emptying and bile stasis. Moreover, devazepide significantly increased hepatic secretion of biliary cholesterol, but not phospholipids or bile salts. The percentage of intestinal cholesterol absorption was higher in devazepide-treated mice, increasing the bioavailability of chylomicron-derived cholesterol in the liver for biliary hypersecretion into bile. These abnormalities induced supersaturated bile and rapid cholesterol crystallization. The potent CCK-1R antagonist devazepide increases susceptibility to gallstone formation by impairing gallbladder emptying function, disrupting biliary cholesterol metabolism and enhancing intestinal cholesterol absorption in mice.

Expression of Human NSAID Activated Gene 1 in Mice Leads to Altered Mammary Gland Differentiation and Impaired Lactation.

Transgenic mice expressing human non-steroidal anti-inflammatory drug activated gene 1 (NAG-1) have less adipose tissue, improved insulin sensitivity, lower insulin levels and are resistant to dietary induced obesity. The hNAG-1 expressing mice are more metabolically active with a higher energy expenditure. This study investigates female reproduction in the hNAG-1 transgenic mice and finds the female mice are fertile but have reduced pup survival after birth. Examination of the mammary glands in these mice suggests that hNAG-1 expressing mice have altered mammary epithelial development during pregnancy, including reduced occupancy of the fat pad and increased apoptosis via TUNEL positive cells on lactation day 2. Pups nursing from hNAG-1 expressing dams have reduced milk spots compared to pups nursing from WT dams. When CD-1 pups were cross-fostered with hNAG-1 or WT dams; reduced milk volume was observed in pups nursing from hNAG-1 dams compared to pups nursing from WT dams in a lactation challenge study. Milk was isolated from WT and hNAG-1 dams, and the milk was found to have secreted NAG-1 protein (approximately 25 ng/mL) from hNAG-1 dams. The WT dams had no detectable hNAG-1 in the milk. A decrease in non-esterified free fatty acids in the milk of hNAG-1 dams was observed. Altered milk composition suggests that the pups were receiving inadequate nutrients during perinatal development. To examine this hypothesis serum was isolated from pups and clinical chemistry points were measured. Male and female pups nursing from hNAG-1 dams had reduced serum triglyceride concentrations. Microarray analysis revealed that genes involved in lipid metabolism are differentially expressed in hNAG-1 mammary glands. Furthermore, the expression of Cidea/CIDEA that has been shown to regulate milk lipid secretion in the mammary gland was reduced in hNAG-1 mammary glands. This study suggests that expression of hNAG-1 in mice leads to impaired lactation and reduces pup survival due to altered milk quality and quantity.

Transcriptome-Wide Analysis Reveals the Role of PPARγ Controlling the Lipid Metabolism in Goat Mammary Epithelial Cells.

To explore the large-scale effect of peroxisome proliferator-activated receptor γ (PPARG) in goat mammary epithelial cells (GMEC), an oligonucleotide microarray platform was used for transcriptome profiling in cells overexpressing PPARG and incubated with or without rosiglitazone (ROSI, a PPARγ agonist). A total of 1143 differentially expressed genes (DEG) due to treatment were detected. The Dynamic Impact Approach (DIA) analysis uncovered the most impacted and induced pathways “fatty acid elongation in mitochondria,” “glycosaminoglycan biosynthesis-keratan sulfate,” and “pentose phosphate pathway.” The data highlights the central role of PPARG in milk fatty acid metabolism via controlling fatty acid elongation, biosynthesis of unsaturated fatty acid, lipid formation, and lipid secretion; furthermore, its role related to carbohydrate metabolism promotes the production of intermediates required for milk fat synthesis. Analysis of upstream regulators indicated that PPARG participates in multiple physiological processes via controlling or cross talking with other key transcription factors such as PPARD and NR1H3 (also known as liver-X-receptor-α). This transcriptome-wide analysis represents the first attempt to better understand the biological relevance of PPARG expression in ruminant mammary cells. Overall, the data underscored the importance of PPARG in mammary lipid metabolism and transcription factor control.

From the Editor’s desk....: January 2016

Selection of the month Plasma exchange improves survival of ALF patients and liver derived exosomes can improve hepatic regeneration Despite improvements in our understanding of acute liver failure, mortality of patients without liver transplantation remains unacceptably high. The study of Larsen et al. describes the results of a landmark randomized clinical trial that took over 10-years to perform and shows that treatment with plasma exchange can improve the survival of ALF patients , providing proof of concept for ‘detoxification' systems.

Transgenic overexpression of Niemann-Pick C2 protein promotes cholesterol gallstone formation in mice

Niemann-Pick C2 (NPC2) is a lysosomal protein involved in the egress of low-density lipoprotein-derived cholesterol from lysosomes to other intracellular compartments. NPC2 has been detected in several tissues and is also secreted from the liver into bile. We have previously shown that NPC2-deficient mice fed a lithogenic diet showed reduced biliary cholesterol secretion as well as cholesterol crystal and gallstone formation. This study aimed to investigate the consequences of NPC2 hepatic overexpression on liver cholesterol metabolism, biliary lipid secretion, gallstone formation and the effect of NPC2 on cholesterol crystallization in model bile. We generated NPC2 transgenic mice (Npc2.Tg) and fed them either chow or lithogenic diets. We studied liver cholesterol metabolism, biliary lipid secretion, bile acid composition and gallstone formation. We performed cholesterol crystallization studies in model bile using a recombinant NPC2 protein. No differences were observed in biliary cholesterol content or secretion between wild-type and Npc2.Tg mice fed the chow or lithogenic diets. Interestingly, Npc2.Tg mice showed an increased susceptibility to the lithogenic diet, developing more cholesterol gallstones at early times, but did not show differences in the bile acid hydrophobicity and gallbladder cholesterol saturation indices compared to wild-type mice. Finally, recombinant NPC2 decreased nucleation time in model bile. These results suggest that NPC2 promotes cholesterol gallstone formation by decreasing the cholesterol nucleation time, indicating a pro-nucleating function of NPC2 in bile.

Morphology, secretion composition, and ecological aspects of stipular colleters in Rubiaceae species from tropical forest and savanna.

Colleters are secretory structures that produce and release mucilage or a mucilage-resin mixture protecting meristems and young structures against desiccation, herbivores, and pathogens. The secretions may vary in colleters of same or different types, indicating that the functionality of colleters may be more specific than previously thought. In this study, we compared 17 Rubiaceae species from savanna and forest environment focusing on colleter secretions and its ecological role. First, we evaluated the morphology, distribution, and histochemistry of stipular colleters using light and scanning electron microscopy. Additionally, we investigated the phenology, microclimate, and the proportion of damaged apices in the savanna and forest species. We recorded standard-type colleters, variable in distribution and size, in 14 of the 17 studied species. The secretion varied from predominantly hydrophilic, mixed to predominantly lipophilic. During the budding period, secretion covered the vegetative apices. Savanna species had a prevalence of lipid secretion in habitats with higher luminosity, which had a lower proportion of damaged apices. In contrast, forest species occurred in habitats with lower luminosity and had a higher proportion of damaged apices, in general with the absence of lipids in the colleters. These results highlight that colleters with similar morphology clearly differed in secretions among species, especially between species from savanna and forest, in which the colleters appear potentially associated with protection against irradiation in savanna, but not in the forest environment.