Impaired liver regeneration and lipid homeostasis in CCl4 treated WDR13 deficient mice

AbstractWDR13 - a WD repeat protein, is abundant in pancreas, liver, ovary and testis. Absence of this protein in mice has been seen to be associated with pancreatic β-cell proliferation, hyperinsulinemia and age dependent mild obesity. Previously, we have reported that the absence of WDR13 in diabetic Leprdb/db mice helps in amelioration of fatty liver phenotype along with diabetes and systemic inflammation. This intrigued us to study direct liver injury and hepatic regeneration in Wdr13−/0 mice using hepatotoxin CCl4. In the present study we report slower hepatic regeneration in Wdr13−/0 mice as compared to their wild type littermates after CCl4 administration. Interestingly, during the regeneration phase, hepatic hypertriglyceridemia was observed in Wdr13−/0 mice. Further analyses revealed an upregulation of PPAR pathway in the liver of CCl4- administered Wdr13−/0 mice, causing de novo lipogenesis. The slower hepatic regeneration observed in CCl4 administered Wdr13−/0 mice, may be linked to liver hypertriglyceridemia because of activation of PPAR pathway.

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Impaired liver regeneration and lipid homeostasis in CCl4 treated WDR13 deficient mice

10.1101/763433 ◽

2019 ◽

Cited By ~ 1

Author(s):

Arun Prakash Mishra ◽

Archana B Siva ◽

Chandrashekaran Gurunathan ◽

Y Komala ◽

B Jyothi Lakshmi

Keyword(s):

De Novo ◽

Recovery Period ◽

Lipid Homeostasis ◽

Hepatic Regeneration ◽

Impaired Liver ◽

Age Dependent ◽

Regeneration Phase ◽

Mild Obesity ◽

Deficient Mice ◽

Ppar Pathway

AbstractBackground and AimWDR13 - a WD repeat protein, is abundant in pancreas, liver, ovary and testis. Absence of this protein in mice has been seen to be associated with pancreatic β-cell proliferation, hyperinsulinemia and age dependent mild obesity. Previously, we have reported that the absence of WDR13 in diabetic Leprdb/db mice helps in amelioration of fatty liver phenotype along with diabetes and systemic inflammation. This intrigued us to study direct liver injury and hepatic regeneration in Wdr13−/0 mice using hepatotoxin CCl4.MethodsMice were injected with CCl4 twice a week for 8 consecutive weeks. Controls were injected with vehicle (olive oil) similarly. After the last injection, mice were given a 10-days of recovery period and then sacrificed for physiological and molecular analyses.ResultsIn the present study we report slower hepatic regeneration in Wdr13−/0 mice as compared to their wild type littermates after CCl4 administration. Interestingly, during the regeneration phase, hepatic hypertriglyceridemia was observed in Wdr13−/0 mice. Further analyses revealed an upregulation of PPAR pathway in the liver of CCl4-administered Wdr13−/0 mice, causing de novo lipogenesis.ConclusionsThe slower hepatic regeneration observed in CCl4 administered Wdr13−/0 mice, may be linked to liver hypertriglyceridemia because of activation of PPAR pathway.

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Hepatic De Novo Lipogenesis Is Present in Liver-Specific ACC1-Deficient Mice

Molecular and Cellular Biology ◽

10.1128/mcb.00304-07 ◽

2007 ◽

Vol 27 (9) ◽

pp. 3556-3556

Author(s):

Naomoto Harada ◽

Zenjun Oda ◽

Yoshikazu Hara ◽

Koji Fujinami ◽

Mayumi Okawa ◽

...

Keyword(s):

De Novo ◽

De Novo Lipogenesis ◽

Deficient Mice

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The peroxisomal transporter ABCD3 plays a major role in dicarboxylic fatty acid metabolism

10.1101/2021.07.26.452046 ◽

2021 ◽

Author(s):

Pablo Ranea-Robles ◽

Hongjie Chen ◽

Brandon Stauffer ◽

Chunli Yu ◽

Dipankar Bhattacharya ◽

...

Keyword(s):

Fatty Acids ◽

De Novo ◽

Ketone Bodies ◽

De Novo Lipogenesis ◽

Lipid Homeostasis ◽

Hepatic Cholesterol Synthesis ◽

Specific Subset

Peroxisomes metabolize a specific subset of fatty acids, which include dicarboxylic fatty acids (DCAs) generated by ω-oxidation. Data obtained in vitro suggest that the peroxisomal transporter ABCD3 (also known as PMP70) mediates the transport of DCAs into the peroxisome, but in vivo evidence to support this role is lacking. In this study, we studied an Abcd3 KO mouse model generated by CRISPR-Cas9 technology using targeted and untargeted metabolomics, histology, immunoblotting, and stable isotope tracing technology. We show that ABCD3 functions in DCA metabolism and uncover a novel role for this peroxisomal transporter in lipid metabolic homeostasis. The Abcd3 KO mouse presents with lipodystrophy, increased circulating free fatty acids, decreased ketone bodies, enhanced hepatic cholesterol synthesis and decreased hepatic de novo lipogenesis. Moreover, our study suggests that DCAs are metabolized by mitochondrial β-oxidation when ABCD3 is not functional, reflecting the importance of the metabolic compartmentalization and communication between peroxisomes and mitochondria. In summary, this study provides data on the role of the peroxisomal transporter ABCD3 in hepatic lipid homeostasis and DCA metabolism, and the consequences of peroxisomal dysfunction for the liver.

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Hepatocyte-Specific Phgdh-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation

Nutrients ◽

10.3390/nu13103468 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3468

Author(s):

Momoko Hamano ◽

Kayoko Esaki ◽

Kazuki Moriyasu ◽

Tokio Yasuda ◽

Sinya Mohri ◽

...

Keyword(s):

Insulin Resistance ◽

Stress Responses ◽

De Novo ◽

Molecular Signatures ◽

Significant Gain ◽

Phosphoglycerate Dehydrogenase ◽

Protein Free Diet ◽

Protein Starvation ◽

Mild Obesity ◽

Deficient Mice

L-Serine (Ser) is synthesized de novo from 3-phosphoglycerate via the phosphorylated pathway committed by phosphoglycerate dehydrogenase (Phgdh). A previous study reported that feeding a protein-free diet increased the enzymatic activity of Phgdh in the liver and enhanced Ser synthesis in the rat liver. However, the nutritional and physiological functions of Ser synthesis in the liver remain unclear. To clarify the physiological significance of de novo Ser synthesis in the liver, we generated liver hepatocyte-specific Phgdh KO (LKO) mice using an albumin-Cre driver. The LKO mice exhibited a significant gain in body weight compared to Floxed controls at 23 weeks of age and impaired systemic glucose metabolism, which was accompanied by diminished insulin/IGF signaling. Although LKO mice had no apparent defects in steatosis, the molecular signatures of inflammation and stress responses were evident in the liver of LKO mice. Moreover, LKO mice were more vulnerable to protein starvation than the Floxed mice. These observations demonstrate that Phgdh-dependent de novo Ser synthesis in liver hepatocytes contributes to the maintenance of systemic glucose tolerance, suppression of inflammatory response, and resistance to protein starvation.

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Oleate activates SREBP-1 signaling activity in SCD1-deficient hepatocytes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00151.2017 ◽

2017 ◽

Vol 313 (6) ◽

pp. E710-E720 ◽

Cited By ~ 18

Author(s):

Mohamed A. Lounis ◽

Karl-F. Bergeron ◽

Maggie S. Burhans ◽

James M. Ntambi ◽

Catherine Mounier

Keyword(s):

Hepg2 Cells ◽

De Novo ◽

Fatty Acid Content ◽

Monounsaturated Fatty Acids ◽

De Novo Lipogenesis ◽

Nuclear Accumulation ◽

Polyunsaturated Fatty Acid Content ◽

Element Binding Protein ◽

Deficient Mice ◽

Signaling Activity

Stearoyl-CoA desaturase-1 (SCD1) is a key player in lipid metabolism. SCD1 catalyzes the synthesis of monounsaturated fatty acids (MUFA). MUFA are then incorporated into triacylglycerols and phospholipids. Previous studies have shown that Scd1 deficiency in mice induces metabolic changes in the liver characterized by a decrease in de novo lipogenesis and an increase in β-oxidation. Interestingly, Scd1-deficient mice show a decrease in the expression and maturation of the principal lipogenic transcription factor sterol receptor element binding protein-1 (SREBP-1). The mechanisms mediating this effect on de novo lipogenesis and β-oxidation have not been fully elucidated. We evaluated the role of SCD1 on de novo lipogenesis and β-oxidation in HepG2 cells. We also used Scd1-deficient mice and two strains of transgenic mice that produce either oleate (GLS5) or palmitoleate (GLS3) in a liver-specific manner. We demonstrate that the expression of β-oxidation markers increases in SCD1-deficient hepatocytes and suggest that this is due to an increase in cellular polyunsaturated fatty acid content. We also show that the changes in the level of SREBP-1 expression, for both the precursor and the mature forms, are mainly due to the lack of oleate in SCD1-deficient hepatocytes. Indeed, oleate treatment of cultured HepG2 cells or hepatic oleate production in chow-fed GLS5 mice can restore SREBP-1 expression and increase hepatic de novo lipogenesis. Finally, we show that oleate specifically increases SREBP-1 nuclear accumulation, suggesting a central role for oleate in SREBP-1 signaling activity.

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Changes in LXR signaling influence early-pregnancy lipogenesis and protect against dysregulated fetoplacental lipid homeostasis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00449.2016 ◽

2017 ◽

Vol 313 (4) ◽

pp. E463-E472 ◽

Cited By ~ 9

Author(s):

Vanya Nikolova ◽

Georgia Papacleovoulou ◽

Elena Bellafante ◽

Luiza Borges Manna ◽

Eugene Jansen ◽

...

Keyword(s):

Early Pregnancy ◽

Fatty Acid Biosynthesis ◽

De Novo ◽

Fetal Liver ◽

Protein Quantification ◽

Cholesterol Homeostasis ◽

De Novo Lipogenesis ◽

Lipid Homeostasis ◽

Genetic Ablation ◽

X Receptors

Human pregnancy is associated with enhanced de novo lipogenesis in the early stages followed by hyperlipidemia during advanced gestation. Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that stimulate de novo lipogenesis and also promote the efflux of cholesterol from extrahepatic tissues followed by its transport back to the liver for biliary excretion. Although LXR is recognized as a master regulator of triglyceride and cholesterol homeostasis, it is unknown whether it facilitates the gestational adaptations in lipid metabolism. To address this question, biochemical profiling, protein quantification, and gene expression studies were used, and gestational metabolic changes in T0901317-treated wild-type mice and Lxrab−/− mutants were investigated. Here, we show that altered LXR signaling contributes to the enhanced lipogenesis in early pregnancy by increasing the expression of hepatic Fas and stearoyl-CoA desaturase 1 ( Scd1). Both the pharmacological activation of LXR with T0901317 and the genetic ablation of its two isoforms disrupted the increase in hepatic fatty acid biosynthesis and the development of hypertriglyceridemia during early gestation. We also demonstrate that absence of LXR enhances maternal white adipose tissue lipolysis, causing abnormal accumulation of triglycerides, cholesterol, and free fatty acids in the fetal liver. Together, these data identify LXR as an important factor in early-pregnancy lipogenesis that is also necessary to protect against abnormalities in fetoplacental lipid homeostasis.

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Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children

Translational Psychiatry ◽

10.1038/tp.2017.27 ◽

2017 ◽

Vol 7 (2) ◽

pp. e1043-e1043 ◽

Cited By ~ 30

Author(s):

I Gozes ◽

A Van Dijck ◽

G Hacohen-Kleiman ◽

I Grigg ◽

G Karmon ◽

...

Keyword(s):

De Novo ◽

Treatment Plan ◽

Gene Array ◽

Autism Spectrum ◽

Tooth Eruption ◽

Primary Tooth ◽

Time Range ◽

Bone Maintenance ◽

Age Dependent ◽

Deficient Mice

Abstract A major flaw in autism spectrum disorder (ASD) management is late diagnosis. Activity-dependent neuroprotective protein (ADNP) is a most frequent de novo mutated ASD-related gene. Functionally, ADNP protects nerve cells against electrical blockade. In mice, complete Adnp deficiency results in dysregulation of over 400 genes and failure to form a brain. Adnp haploinsufficiency results in cognitive and social deficiencies coupled to sex- and age-dependent deficits in the key microtubule and ion channel pathways. Here, collaborating with parents/caregivers globally, we discovered premature tooth eruption as a potential early diagnostic biomarker for ADNP mutation. The parents of 44/54 ADNP-mutated children reported an almost full erupted dentition by 1 year of age, including molars and only 10 of the children had teeth within the normal developmental time range. Looking at Adnp-deficient mice, by computed tomography, showed significantly smaller dental sacs and tooth buds at 5 days of age in the deficient mice compared to littermate controls. There was only trending at 2 days, implicating age-dependent dysregulation of teething in Adnp-deficient mice. Allen Atlas analysis showed Adnp expression in the jaw area. RNA sequencing (RNAseq) and gene array analysis of human ADNP-mutated lymphoblastoids, whole-mouse embryos and mouse brains identified dysregulation of bone/nervous system-controlling genes resulting from ADNP mutation/deficiency (for example, BMP1 and BMP4). AKAP6, discovered here as a major gene regulated by ADNP, also links cognition and bone maintenance. To the best of our knowledge, this is the first time that early primary (deciduous) teething is related to the ADNP syndrome, providing for early/simple diagnosis and paving the path to early intervention/specialized treatment plan.

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Hepatic De Novo Lipogenesis Is Present in Liver-Specific ACC1-Deficient Mice

Molecular and Cellular Biology ◽

10.1128/mcb.01122-06 ◽

2007 ◽

Vol 27 (5) ◽

pp. 1881-1888 ◽

Cited By ~ 75

Author(s):

Naomoto Harada ◽

Zenjun Oda ◽

Yoshikazu Hara ◽

Koji Fujinami ◽

Mayumi Okawa ◽

...

Keyword(s):

Fatty Acid Synthase ◽

De Novo ◽

Physiological Role ◽

De Novo Lipogenesis ◽

Null Mouse ◽

Acetyl Coa ◽

Dual Inhibitor ◽

Malonyl Coa ◽

Deficient Mice

ABSTRACT Acetyl coenzyme A (acetyl-CoA) carboxylase (ACC) catalyzes carboxylation of acetyl-CoA to form malonyl-CoA. In mammals, two isozymes exist with distinct physiological roles: cytosolic ACC1 participates in de novo lipogenesis (DNL), and mitochondrial ACC2 is involved in negative regulation of mitochondrial β-oxidation. Since systemic ACC1 null mice were embryonic lethal, to clarify the physiological role of ACC1 in hepatic DNL, we generated the liver-specific ACC1 null mouse by crossbreeding of an Acc1 lox(ex46) mouse, in which exon 46 of Acc1 was flanked by two loxP sequences and the liver-specific Cre transgenic mouse. In liver-specific ACC1 null mice, neither hepatic Acc1 mRNA nor protein was detected. However, to compensate for ACC1 function, hepatic ACC2 protein and activity were induced 1.4 and 2.2 times, respectively. Surprisingly, hepatic DNL and malonyl-CoA were maintained at the same physiological levels as in wild-type mice. Furthermore, hepatic DNL was completely inhibited by an ACC1/2 dual inhibitor, 5-tetradecyloxyl-2-furancarboxylic acid. These results strongly demonstrate that malonyl-CoA from ACC2 can access fatty acid synthase and become the substrate for the DNL pathway under the unphysiological circumstances that result with ACC1 disruption. Therefore, there does not appear to be strict compartmentalization of malonyl-CoA from either of the ACC isozymes in the liver.

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