scholarly journals Hydroxysteroid (17β) dehydrogenase 12 is essential for metabolic homeostasis in adult mice

2020 ◽  
Vol 319 (3) ◽  
pp. E494-E508 ◽  
Author(s):  
Hanna Heikelä ◽  
Suvi T. Ruohonen ◽  
Marion Adam ◽  
Riikka Viitanen ◽  
Heidi Liljenbäck ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Toxicity ◽  
Sickness Behavior ◽  
Gene Inactivation ◽  
Lipid Homeostasis ◽  
Mouse Development ◽  
Adult Mice ◽  
Carbon Fatty Acid ◽  
Food And Water Intake ◽  
Stimulating Factor

Hydroxysteroid 17β dehydrogenase 12 (HSD17B12) is suggested to be involved in the elongation of very long chain fatty acids. Previously, we have shown a pivotal role for the enzyme during mouse development. In the present study we generated a conditional Hsd17b12 knockout (HSD17B12cKO) mouse model by breeding mice homozygous for a floxed Hsd17b12 allele with mice expressing the tamoxifen-inducible Cre recombinase at the ROSA26 locus. Gene inactivation was induced by administering tamoxifen to adult mice. The gene inactivation led to a 20% loss of body weight within 6 days, associated with drastic reduction in both white (83% males, 75% females) and brown (65% males, 60% females) fat, likely due to markedly reduced food and water intake. Furthermore, the knockout mice showed sickness behavior and signs of liver toxicity, specifically microvesicular hepatic steatosis and increased serum alanine aminotransferase (4.6-fold in males, 7.7-fold in females). The hepatic changes were more pronounced in females than males. Proinflammatory cytokines, such as interleukin-6 (IL-6), IL-17, and granulocyte colony-stimulating factor, were increased in the HSD17B12cKO mice indicating an inflammatory response. Serum lipidomics study showed an increase in the amount of dihydroceramides, despite the dramatic overall loss of lipids. In line with the proposed role for HSD17B12 in fatty acid elongation, we observed accumulation of ceramides, dihydroceramides, hexosylceramides, and lactosylceramides with shorter than 18-carbon fatty acid side chains in the serum. The results indicate that HSD17B12 is essential for proper lipid homeostasis and HSD17B12 deficiency rapidly results in fatal systemic inflammation and lipolysis in adult mice.

scholarly journals Can granulocyte colony stimulating factor (G-CSF) ameliorate acetaminophen-induced hepatotoxicity?

2021 ◽  
pp. 096032712110085
Author(s):  
EA Ahmed ◽  
AM Abd-Eldayem ◽  
E Ahmed
Keyword(s):  
Liver Damage ◽  
Liver Toxicity ◽  
Serum Levels ◽  
Hepatic Tissue ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Oxidative Markers ◽  
Stimulating Factor ◽  
New Strategies ◽  
Factor G

Acetaminophen (APAP) is often used as an antipyretic and analgesic agent. Overdose hepatotoxicity, which often results in liver cell failure and liver transplantation, is a severe complication of APAP usage. To save the liver and save lives from acute liver damage caused by APAP, the search for new strategies for liver defense is important. Wistar rats have been used for the induction of APAP hepatotoxicity. Elevated levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were evaluated for liver toxicity. In addition, the levels of hepatic tissue oxidative markers such as malondialdehyde (MDA), nitric oxide (NO) increased while glutathione (GSH) was depleted and catalase (CAT) activity was curtailed. The biochemical findings were consistent with the changes in histology that suggested liver damage and inflammation. Treated rats with N-acetylcysteine (N-AC) and granulocyte colony stimulating factor (G-CSF) showed a decrease in serum levels of ALT, AST and LDH, while the level of ALP in the G-CSF group was still high. After administration of APAP, treatment with N-AC or G-CSF substantially reduced the level of MDA and NO while maintaining the GSH content and CAT activity. Treatment with N-AC and G-CSF after administration of APAP has also attenuated inflammation and hepatocytes necrosis. The results of this study showed that G-CSF could be viewed as an alternative hepatoprotective agent against APAP-induced acute liver injury compared to N-AC.

scholarly journals The SH2-Containing Inositol Polyphosphate 5-Phosphatase, Ship, Is Expressed During Hematopoiesis and Spermatogenesis

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2753-2759 ◽  
Author(s):  
Qiurong Liu ◽  
Fouad Shalaby ◽  
Jamie Jones ◽  
Denis Bouchard ◽  
Daniel J. Dumont
Keyword(s):  
Primitive Streak ◽  
Inositol Polyphosphate ◽  
Mouse Development ◽  
Developmentally Regulated ◽  
Adult Mice ◽  
Expression Studies ◽  
Cell Culture Systems ◽  
Physiologic Function ◽  
T Cell Maturation

Ship is a recently identified SH2-containing inositol polyphosphate 5-phosphatase that has been implicated as an important signaling molecule in cell-culture systems. To understand the physiologic function of Ship in vivo, we performed expression studies of Ship during mouse development. Results of this study demonstrate the expression of ship to be in late primitive-streak stage embryos (7.5 days postcoitus [dpc]), when hematopoiesis is thought to begin, and the expression is restricted to the hematopoietic lineage in mouse embryo. In adult mice, Ship expression continues to be in the majority of cells from hematopoietic origin, including granulocytes, monocytes, and lymphocytes, and is also found in the spermatids of the testis. Furthermore, the level of Ship expression is developmentally regulated during T-cell maturation. These results suggest a possible role for Ship in the differentiation and maintenance of the hematopoietic lineages and in spermatogenesis.

Circulating granulocyte-macrophage colony-stimulating factor and serum fatty acid composition in men and women

Metabolism ◽  
2001 ◽  
Vol 50 (12) ◽  
pp. 1479-1483 ◽  
Author(s):  
Jos[eacute]-Manuel Fern[aacute]ndez-Real ◽  
Montserrat Vayreda ◽  
Roser Casamitjana ◽  
Ferran Gonzalez-Huix ◽  
Wifredo Ricart
Keyword(s):  
Fatty Acid Composition ◽  
Fatty Acid ◽  
Acid Composition ◽  
Colony Stimulating Factor ◽  
Serum Fatty Acid ◽  
Men And Women ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Serum Fatty Acid Composition

scholarly journals Stimulation of fetal hemoglobin production by short chain fatty acids

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3227-3235 ◽  
Author(s):  
E Liakopoulou ◽  
CA Blau ◽  
Q Li ◽  
B Josephson ◽  
JA Wolf ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Erythroid Cell ◽  
Gamma Globin ◽  
Carbon Fatty Acid ◽  
Chain Fatty Acids

Abstract Butyrate, a four-carbon fatty acid, and its two-carbon metabolic product, acetate, are inducers of gamma-globin synthesis. To test whether other short-chain fatty acids share this property, we first examined whether propionic acid, a three-carbon fatty acid that is not catabolized to acetate, induces gamma-globin expression. Sodium propionate increased the frequency of fetal hemoglobin containing erythroblasts and the gamma/gamma + beta mRNA ratios in adult erythroid cell cultures and F reticulocyte production in a nonanemic juvenile baboon. Short-chain fatty acids containing five (pentanoic), six (hexanoic), seven (heptanoic), eight (octanoic), and nine (nonanoic) carbons induced gamma-globin expression (as measured by increase in gamma-positive erythroblasts and gamma/gamma + beta mRNA ratios) in adult erythroid burst-forming unit cultures. There was a clear-cut relationship between the concentration of fatty acids in culture and the degree of induction of gamma-globin expression. Three-, four-, and five-carbon fatty acids were better inducers of gamma globin in culture as compared with six- to nine-carbon fatty acids. These results suggest that all short-chain fatty acids share the property of gamma-globin gene inducibility. The fact that valproic acid, a derivative of pentanoic acid, also induces gamma-globin expression suggests that short-chain fatty acid derivatives that are already approved for human use may possess the property of gamma-globin inducibility and may be of therapeutic relevance to the beta-chain hemoglobinopathies.

scholarly journals Aging Influences the Metabolic and Inflammatory Phenotype in an Experimental Mouse Model of Acute Lung Injury

2020 ◽  
Author(s):  
Kevin W Gibbs ◽  
Chia-Chi Chuang Key ◽  
Lanazha Belfield ◽  
Jennifer Krall ◽  
Lina Purcell ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Fatty Acid ◽  
Lung Injury ◽  
Whole Body ◽  
Acid Oxidation ◽  
Aged Mice ◽  
Protein Levels ◽  
Adult Mice ◽  
Age Related ◽  
Before And After

Abstract Increased age is a risk factor for poor outcomes from respiratory failure and acute respiratory distress syndrome (ARDS). In this study, we sought to define age-related differences in lung inflammation, muscle injury, and metabolism after intratracheal lipopolysaccharide (IT-LPS) acute lung injury (ALI) in adult (6 months) and aged (18–20 months) male C57BL/6 mice. We also investigated age-related changes in muscle fatty acid oxidation (FAO) and the consequences of systemic FAO inhibition with the drug etomoxir. Aged mice had a distinct lung injury course characterized by prolonged alveolar neutrophilia and lack of response to therapeutic exercise. To assess the metabolic consequences of ALI, aged and adult mice underwent whole body metabolic phenotyping before and after IT-LPS. Aged mice had prolonged anorexia and decreased respiratory exchange ratio, indicating increased reliance on FAO. Etomoxir increased mortality in aged but not adult ALI mice, confirming the importance of FAO on survival from acute severe stress and suggesting that adult mice have increased resilience to FAO inhibition. Skeletal muscles from aged ALI mice had increased transcription of key fatty acid metabolizing enzymes, CPT-1b, LCAD, MCAD, FATP1 and UCP3. Additionally, aged mice had increased protein levels of CPT-1b at baseline and after lung injury. Surprisingly, CPT-1b in isolated skeletal muscle mitochondria had decreased activity in aged mice compared to adults. The distinct phenotype of aged ALI mice has similar characteristics to the adverse age-related outcomes of ARDS. This model may be useful to examine and augment immunologic and metabolic abnormalities unique to the critically ill aged population.

scholarly journals Role of the Gut in Lipid Homeostasis

2012 ◽  
Vol 92 (3) ◽  
pp. 1061-1085 ◽  
Author(s):  
Nada A. Abumrad ◽  
Nicholas O. Davidson
Keyword(s):  
Fatty Acid ◽  
Genetic Regulation ◽  
Density Lipoprotein ◽  
Microsomal Triglyceride Transfer Protein ◽  
Cholesterol Absorption ◽  
Lessons Learned ◽  
Lipid Homeostasis ◽  
Integrative View ◽  
Familial Hypobetalipoproteinemia

Intestinal lipid transport plays a central role in fat homeostasis. Here we review the pathways regulating intestinal absorption and delivery of dietary and biliary lipid substrates, principally long-chain fatty acid, cholesterol, and other sterols. We discuss the regulation and functions of CD36 in fatty acid absorption, NPC1L1 in cholesterol absorption, as well as other lipid transporters including FATP4 and SRB1. We discuss the pathways of intestinal sterol efflux via ABCG5/G8 and ABCA1 as well as the role of the small intestine in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. We review the pathways and genetic regulation of chylomicron assembly, the role of dominant restriction points such as microsomal triglyceride transfer protein and apolipoprotein B, and the role of CD36, l-FABP, and other proteins in formation of the prechylomicron complex. We will summarize current concepts of regulated lipoprotein secretion (including HDL and chylomicron pathways) and include lessons learned from families with genetic mutations in dominant pathways (i.e., abetalipoproteinemia, chylomicron retention disease, and familial hypobetalipoproteinemia). Finally, we will provide an integrative view of intestinal lipid homeostasis through recent findings on the role of lipid flux and fatty acid signaling via diverse receptor pathways in regulating absorption and production of satiety factors.

scholarly journals An Eight-Residue Deletion in Escherichia coli FabG Causes Temperature-Sensitive Growth and Lipid Synthesis Plus Resistance to the Calmodulin Inhibitor Trifluoperazine

2017 ◽  
Vol 199 (10) ◽  
Author(s):  
Swaminath Srinivas ◽  
John E. Cronan
Keyword(s):  
Fatty Acid ◽  
Structural Dynamics ◽  
Active Site ◽  
Lipid A ◽  
Acid Synthesis ◽  
Lipid Homeostasis ◽  
Temperature Sensitive ◽  
Active Site Cleft

ABSTRACT FabG performs the NADPH-dependent reduction of β-keto acyl-acyl carrier protein substrates in the elongation cycle of fatty acid synthesis. We report the characterization of a temperature-sensitive mutation (fabGΔ8) in Escherichia coli fabG that results from an in-frame 8-amino-acid residue deletion in the α6/α7 subdomain. This region forms part of one of the two dimerization interfaces of this tetrameric enzyme and is reported to undergo significant conformational changes upon cofactor binding, which define the entrance to the active-site cleft. The activity of the mutant enzyme is extremely thermolabile and is deficient in forming homodimers at nonpermissive temperatures with a corresponding decrease in fatty acid synthesis both in vivo and in vitro. Surprisingly, the fabGΔ8 strain reverts to temperature resistance at a rate reminiscent of that of a point mutant with intragenic pseudorevertants located either on the 2-fold axes of symmetry or at the mouth of the active-site cleft. The fabGΔ8 mutation also confers resistance to the calmodulin inhibitor trifluoperazine and renders the enzyme extremely sensitive to Ca2+ in vitro. We also observed a significant alteration in the lipid A fatty acid composition of fabGΔ8 strains but only in an lpxC background, probably due to alterations in the permeability of the outer membrane. These observations provide insights into the structural dynamics of FabG and hint at yet another point of regulation between fatty acid and lipid A biosynthesis. IMPORTANCE Membrane lipid homeostasis and its plasticity in a variety of environments are essential for bacterial survival. Since lipid biosynthesis in bacteria and plants is fundamentally distinct from that in animals, it is an ideal target for the development of antibacterial therapeutics. FabG, the subject of this study, catalyzes the first cofactor-dependent reduction in this pathway and is active only as a tetramer. This study examines the interactions responsible for tetramerization through the biochemical characterization of a novel temperature-sensitive mutation caused by a short deletion in an important helix-turn-helix motif. The mutant strain has altered phospholipid and lipid A compositions and is resistant to trifluoperazine, an inhibitor of mammalian calmodulin. Understanding its structural dynamics and its influence on lipid A synthesis also allows us to explore lipid homeostasis as a mechanism for antibiotic resistance.

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