Prohibitin Inactivation in Adipocytes Results in Reduced Lipid Metabolism and Adaptive Thermogenesis Impairment

Prohibitin-1 (PHB) is a multifunctional protein previously reported to be important for adipocyte function. PHB is expressed on the surface of adipose cells, where it interacts with a long chain fatty acid (LCFA) transporter. Here, we show that mice lacking PHB in adipocytes (PHB Ad-KO) have a defect in fat tissue accumulation despite having larger lipid droplets in adipocytes due to reduced lipolysis. Although PHB Ad-KO mice do not display glucose intolerance, they are insulin resistant. We show that PHB Ad-KO mice are lipid intolerant due to a decreased capacity of adipocytes for LCFA uptake. Instead, PHB Ad-KO mice have increased expression of glucose transporter GLUT1 in various tissues and use glucose as a preferred energy source. We demonstrate that PHB Ad-KO mice have defective brown AT, are cold-intolerant, and display a reduced basal energy expenditure. Systemic repercussions of PHB inactivation in adipocytes were observed in both males and females. Consistent with lower cellular mitochondrial content and reduced UCP1 protein expression, brown adipocytes lacking PHB display decreased proton leak and switch from aerobic metabolism to glycolysis. Treatment of differentiating brown adipocytes with small molecules targeting PHB suppressed mitochondrial respiration and uncoupling. Our results demonstrate that PHB in adipocytes is essential for normal fatty acid uptake, oxidative metabolism, and adaptive thermogenesis. We conclude that PHB inhibition could be investigated as an approach to altering energy substrate utilization.

Prohibitin Inactivation in Adipocytes Results in Reduced Lipid Metabolism and Adaptive Thermogenesis Impairment

Prohibitin-1 (PHB) is a multifunctional protein previously reported to be important for adipocyte function. PHB is expressed on the surface of adipose cells, where it interacts with a long chain fatty acid (LCFA) transporter. Here, we show that mice lacking PHB in adipocytes (PHB Ad-KO) have a defect in fat tissue accumulation despite having larger lipid droplets in adipocytes due to reduced lipolysis. Although PHB Ad-KO mice do not display glucose intolerance, they are insulin resistant. We show that PHB Ad-KO mice are lipid intolerant due to a decreased capacity of adipocytes for LCFA uptake. Instead, PHB Ad-KO mice have increased expression of glucose transporter GLUT1 in various tissues and use glucose as a preferred energy source. We demonstrate that PHB Ad-KO mice have defective brown AT, are cold-intolerant, and display a reduced basal energy expenditure. Systemic repercussions of PHB inactivation in adipocytes were observed in both males and females. Consistent with lower cellular mitochondrial content and reduced UCP1 protein expression, brown adipocytes lacking PHB display decreased proton leak and switch from aerobic metabolism to glycolysis. Treatment of differentiating brown adipocytes with small molecules targeting PHB suppressed mitochondrial respiration and uncoupling. Our results demonstrate that PHB in adipocytes is essential for normal fatty acid uptake, oxidative metabolism, and adaptive thermogenesis. We conclude that PHB inhibition could be investigated as an approach to altering energy substrate utilization.

Activation of amino acid metabolic program in response to impaired glycolysis in cardiac HIF1 deficient mice

ABSTRACTHypoxia is an important environmental cue in heart development. Despite of extensive characterization of gain and loss of function models, there is disagreement about the impact of HIF1α elimination in cardiac tissue. Here, we used a new conditional knock out of Hif1a in NKX2.5 cardiac progenitors to assess the morphological and functional consequences of HIF1α loss in the developing heart. By combining histology, electron microscopy and high-throughout genomics, proteomics and metabolomics, we found that deletion of Hif1a leads to impaired embryonic glycolysis without influencing cardiomyocyte proliferation and results in an increased mitochondrial number, activation of a transient amino acid response and upregulation of HIF2α and ATF4 by E12.5. Hif1a mutants display normal fatty acid oxidation metabolic profile and do not show any sign of cardiac dysfunction in the adulthood. Our results demonstrate that HIF1 signaling is dispensable for heart development and reveal the metabolic flexibility of the embryonic myocardium, opening the potential application of alternative energy sources as therapeutic interventions during ischemic events.

Targeted Metabolomics of Serum Acylcarnitines Evaluates Hepatoprotective Effect of Wuzhi Tablet (Schisandra sphenantheraExtract) against Acute Acetaminophen Toxicity

Possible prevention and therapeutic intervention strategies to counteract acetaminophen (APAP) hepatotoxicity would be of great value. Wuzhi tablet (WZ, extract ofSchisandrae sphenanthera) possesses hepatoprotective effects against hepatitis and the hepatic dysfunction induced by various chemical hepatotoxins. In this study, the protective effect of WZ on APAP-induced hepatic injury was evaluated and targeted metabolomics by LC-MS-based metabolomics was used to examine whether WZ influences hepatic metabolism. The results demonstrated significant hepatoprotection of WZ against APAP-induced liver injury; pretreatment with WZ prior to APAP administration blocks the increase in serum palmitoylcarnitine and oleoylcarnitine and thus restores the APAP-impaired fatty acidβ-oxidation to normal levels. These studies further revealed a significant and prolonged upregulation of the PPARαtarget genesCpt1andAcot1by WZ mainly contributing to the maintenance of normal fatty acid metabolism and thus potentially contributing to the hepatic protection of WZ against APAP-induced hepatic toxicity. Taken together, the current study provides new insights into understanding the hepatoprotective effect of WZ against APAP-induced liver toxicity.

Preparation and Research of the Multifunctional Heat Stabilizer with Rare Earth Used in PVC Products

In this paper, a new heat stabilizer was prepared, which has shown not only excellence thermal stability, but also shown obvious oxidation resistance and anti-aging properties. This multifunctional heat stabilizer was prepared by organic acid, rare earth and thiourea. The lauric acid as best stuff was chosen from some normal fatty acid and lanthanum nitrate as most potent rare earth was picked up too. Using these raw materials, the best heat stabilizer was synthesized under this conditions of synthesizing at 80°C, reacting 40min, adding 1.0mol/L sodium-hydroxide for keeping PH at 8 and making certain the amount of raw material(lauric acid : thiourea : lanthanum nitrate) at the proportion as 4∶1∶1. The thermal stability was examined by the change time of Congo red, and the result proved this heat stabilizer having good thermal stability for up this time to 40min. When this rare earth stabilizer was joined into PVC, the PVC can keep its color not changing during 48h under ultraviolet radiation, and the tensile strength and elongation at break of the PVC added rare stabilizer changed more little under ultraviolet radiation compared with the traditional heat stabilizer system. So this rare earth heat stabilizer acting as a good heat stabilizer, anti-oxidant and anti-aging agent is a new multifunctional heat stabilizer.

Transcriptional and functional characterization of the gene encoding acyl carrier protein in Bacillus subtilis

Acyl carrier protein (ACP) is a universal and highly conserved carrier of acyl intermediates during fatty acid biosynthesis. The molecular mechanisms of regulation of the acpP structural gene, as well as the function of its gene product, are poorly characterized in Bacillus subtilis and other Gram-positive organisms. Here, we report that transcription of acpP takes place from two different promoters: PfapR and PacpP. Expression of acpP from PfapR is coordinated with a cluster of genes involved in lipid synthesis (the fapR operon); the operon consists of fapR-plsX-fabD-fabG-acpP. PacpP is located immediately upstream of the acpP coding sequence, and is necessary and sufficient for normal fatty acid synthesis. We also report that acpP is essential for growth and differentiation, and that ACP localizes in the mother-cell compartment of the sporangium during spore formation. These results provide the first detailed characterization of the expression of the ACP-encoding gene in a Gram-positive bacterium, and highlight the importance of this protein in B. subtilis physiology.

Chemical and volatile composition of three italian sweet white Passito wines

<p style="text-align: justify;"><strong>Aims</strong>: This study was designed to gain knowledge of three Controlled Denomination of Origin (DOC) Italian sweet white Passito wines (Caluso Passito DOC, Cinque Terre Sciacchetrà DOC and Passito di Pantelleria DOC) produced in several areas of Italy from grapes dried with different systems and vinification techniques.</p><p style="text-align: justify;"><strong>Methods and results</strong>: Physico-chemical and chromatic characteristics, sodium, potassium, gluconic acid, glucono-γ-lactone, acetaldehyde, sorbitol, laccase, organic acids and semi-quantitative free volatile profile were determined on these wines. Caluso Passito DOC wines presented higher contents of organic acids (above all, malic acid), main metabolites from noble Botrytis cinerea (laccase, glycerol, gluconic acid and benzaldehyde) and low contents of total polyphenols. Among the volatile components, normal fatty acid ethyl esters (ethyl hexanoate and ethyl octanoate), branched-chain esters (ethyl 2-methylpropanoate, ethyl 2-methylbutyrate, ethyl 3-methylbutyrate) and benzaldeyde characterized this Passito wine. Cinque Terre Sciacchetrà DOC wines showed the lowest total acidity with a lower amount of malic acid and a higher content of polyphenols. This wine was characterized by some predominant acetates (isoamyl acetate), alcohols, benzaldehyde and an isoprenoid, ß-damascenone. Passito di Pantelleria DOC wines presented higher amounts of ashes resulting in higher pH values compared to the other two Passito typologies. Due to its production from aromatic grapes, it showed several varietal components such as terpenes, while ethyl esters/acetates and alcohols were less represented.</p><p style="text-align: justify;"><strong>Conclusion</strong>: This survey provides information allowing the characterisation of three Passito dessert wines at high commercial value.</p><p style="text-align: justify;"><strong>Significance and impact of the study</strong>: This study provides oenological information to be utilised to protect and valorise the Controlled Denomination of Origin sweet wine production and contributes to the preservation of traditional and terroir productions and their commercialization.</p>