scholarly journals MAPK-interacting kinase 2 (MNK2) regulates adipocyte metabolism independently of its catalytic activity

2020 ◽  
Vol 477 (14) ◽  
pp. 2735-2754
Author(s):  
James E. Merrett ◽  
Jianling Xie ◽  
Peter J. Psaltis ◽  
Christopher G. Proud
Keyword(s):  
Catalytic Activity ◽  
Lipid Accumulation ◽  
Adipocyte Differentiation ◽  
De Novo ◽  
Lipid Storage ◽  
De Novo Lipogenesis ◽  
Hormone Sensitive Lipase ◽  
Mitogen Activated Protein Kinase ◽  
Whole Body ◽  
Knock Down

The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are serine/threonine protein kinases that are activated by the ERK1/2 (extracellular regulated kinase) and p38α/β MAPK pathways. The MNKs have previously been implicated in metabolic disease and shown to mediate diet-induced obesity. In particular, knockout of MNK2 in mice protects from the weight gain induced by a high-fat diet. These and other data suggest that MNK2 regulates the expansion of adipose tissue (AT), a stable, long-term energy reserve that plays an important role in regulating whole-body energy homeostasis. Using the well-established mouse 3T3-L1 in vitro model of adipogenesis, the role of the MNKs in adipocyte differentiation and lipid storage was investigated. Inhibition of MNK activity using specific inhibitors failed to impair adipogenesis or lipid accumulation, suggesting that MNK activity is not required for adipocyte differentiation and does not regulate lipid storage. However, small-interfering RNA (siRNA) knock-down of MNK2 did reduce lipid accumulation and regulated the levels of two major lipogenic transcriptional regulators, ChREBP (carbohydrate response element-binding protein) and LPIN1 (Lipin-1). These factors are responsible for controlling the expression of genes for proteins involved in de novo lipogenesis and triglyceride synthesis. The knock-down of MNK2 also increased the expression of hormone-sensitive lipase which catalyses the breakdown of triglyceride. These findings identify MNK2 as a regulator of adipocyte metabolism, independently of its catalytic activity, and reveal some of the mechanisms by which MNK2 drives AT expansion. The development of an MNK2-targeted therapy may, therefore, be a useful intervention for reducing weight caused by excessive nutrient intake.

Effect of carbohydrate intake on de novo lipogenesis in human adipose tissue

1987 ◽  
Vol 253 (6) ◽  
pp. E664-E669 ◽  
Author(s):  
C. Chascione ◽  
D. H. Elwyn ◽  
M. Davila ◽  
K. M. Gil ◽  
J. Askanazi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
De Novo ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Whole Body ◽  
High Intake ◽  
Carbohydrate Diet ◽  
Triglyceride Synthesis ◽  
High Carbohydrate

Rates of synthesis, from [14C]glucose, of fatty acids (de novo lipogenesis) and glycerol (triglyceride synthesis) were measured in biopsies of adipose tissue from nutritionally depleted patients given low- or high-carbohydrate intravenous nutrition. Simultaneously, energy expenditure and whole-body lipogenesis were measured by indirect calorimetry. Rates of whole-body lipogenesis were zero on the low-carbohydrate diet and averaged 1.6 g.kg-1.day-1 on the high-carbohydrate diet. In vitro rates of triglyceride synthesis increased 3-fold going from the low to the high intake; rates of fatty acid synthesis increased approximately 80-fold. In vitro, lipogenesis accounted for less than 0.1% of triglyceride synthesis on the low intake and 4% on the high intake. On the high-carbohydrate intake, in vitro rates of triglyceride synthesis accounted for 61% of the rates of unidirectional triglyceride synthesis measured by indirect calorimetry. In vitro rates of lipogenesis accounted for 7% of whole-body lipogenesis. Discrepancies between in vitro rates of fatty acid synthesis from glucose, compared with acetate and citrate, as reported by others, suggest that in depleted patients on hypercaloric high-carbohydrate diets, adipose tissue may account for up to 40% of whole-body lipogenesis.

scholarly journals In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

2020 ◽  
Vol 21 (4) ◽  
pp. 1206 ◽  
Author(s):  
Luisa Siculella ◽  
Laura Giannotti ◽  
Mariangela Testini ◽  
Gabriele V. Gnoni ◽  
Fabrizio Damiano
Keyword(s):  
Lipid Accumulation ◽  
De Novo ◽  
Cell Model ◽  
Mrna Translation ◽  
De Novo Lipogenesis ◽  
Atp Citrate Lyase ◽  
Entry Site ◽  
Alcoholic Fatty Liver ◽  
Citrate Lyase ◽  
Independent Mechanism

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease in which excessive amount of lipids is accumulated as droplets in hepatocytes. Recently, cumulative evidences suggested that a sustained de novo lipogenesis can play an important role in NAFLD. Dysregulated expression of lipogenic genes, including ATP-citrate lyase (ACLY), has been found in liver diseases associated with lipid accumulation. ACLY is a ubiquitous cytosolic enzyme positioned at the intersection of nutrients catabolism and cholesterol and fatty acid biosyntheses. In the present study, the molecular mechanism of ACLY expression in a cell model of steatosis has been reported. We identified an internal ribosome entry site (IRES) in the 5′ untranslated region of the ACLY mRNA, that can support an efficient mRNA translation through a Cap-independent mechanism. In steatotic HepG2 cells, ACLY expression was up-regulated through IRES-mediated translation. Since it has been demonstrated that lipid accumulation in cells induces endoplasmic reticulum (ER) stress, the involvement of this cellular pathway in the translational regulation of ACLY has been also evaluated. Our results showed that ACLY expression was increased in ER-stressed cells, through IRES-mediated translation of ACLY mRNA. A potential role of the Cap-independent translation of ACLY in NAFLD has been discussed.

Ellagic acid ameliorates AKT-driven hepatic steatosis in mice by suppressing de novo lipogenesis via the AKT/SREBP-1/FASN pathway

2019 ◽  
Vol 10 (6) ◽  
pp. 3410-3420 ◽  
Author(s):  
Cong Zhang ◽  
Junjie Hu ◽  
Lei Sheng ◽  
Ming Yuan ◽  
Yong Wu ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Ellagic Acid ◽  
Lipid Accumulation ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

Ellagic acid alleviates hepatic lipid accumulation in mice by suppressing AKT-driven de novo lipogenesis.

scholarly journals SUN-LB52 The Protective Effects of Hepatocyte GH Receptor (GHR) Signaling Against Steatosis and Liver Injury Is Sexually Dimorphic and Autonomous of IGF1

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Andre Sarmento-Cabral ◽  
Mercedes del Rio-Moreno ◽  
Mari C Vazquez-Borrego ◽  
Mariyah Mahmood ◽  
Elena Gutierrez-Casado ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Injury ◽  
Fatty Liver ◽  
Negative Feedback ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Whole Body ◽  
Chow Diet ◽  
Alcoholic Fatty Liver ◽  
Systemic Insulin Resistance

Abstract GH dysregulation contributes to the development of non-alcoholic fatty liver disease (NAFLD), however debate remains as to the relative contribution of the direct vs indirect effects of GH, via IGF1. Mouse models with congenital, liver-specific knockout of the GHR, JAK2 or STAT5, as adults exhibit steatosis, glucose intolerance, insulin resistance and white adipose tissue (WAT) lipolysis. It is believed that fatty liver is due to the dramatic reduction in circulating IGF1 altering systemic metabolism, due to loss of the insulin-like effects of IGF1 and the loss of IGF1 negative feedback to the pituitary leading to a rise in GH that promotes systemic insulin resistance and WAT lipolysis shifting the flux of fatty acids to the liver. In addition, low IGF1/high GH alters the development of other metabolically relevant tissues, which could indirectly contribute to the liver phenotype observed with congenital loss of hepatic GH signaling. To directly test the actions of GH on adult hepatocyte function, we developed a mouse model of adult-onset, hepatocyte-specific knockdown of the GHR (aHepGHRkd; 12 week-old, GHRfl/fl mice treated with AAV8-TBGp-Cre). aHepGHRkd enhanced hepatic de novo lipogenesis (DNL), rapidly leading to steatosis in males, but not females. In males, enhanced DNL and steatosis was sustained with age and associated with hepatocyte ballooning, inflammation and mild fibrosis. These changes occurred independent of severe systemic insulin resistance and WAT lipolysis, although the aHepGHRkd mice exhibit low IGF1/high GH similar to that of congenital models. To directly test the role of hepatocyte GHR signaling, independent of changes in IGF1, aHepGHRkd mice were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes (AAV8-TBGp-rIGF1). Mice were fed standard chow diet and tissues collected 8m post-AAV. IGF1 replacement elevated plasma IGF1 in aHepGHRkd mice, resulting in a reduction in plasma GH and pituitary expression of Gh, Ghrhr and Ghsr, indicating negative feedback of IGF1 was restored. In male aHepGHRkd mice, IGF1 replacement reduced insulin and whole body lipid utilization and increased WAT, however it did not reduce steatosis or alter hepatic fatty acid composition indicative of DNL and had minimal effects on liver injury markers. RNAseq analysis of liver extracts showed IGF1 replacement also had no major impact on the differentially expressed genes observed after aHepGHRkd. These results demonstrate that steatosis, DNL and liver injury observed in male aHepGHRkd mice are autonomous of IGF1. Despite the fact that hepatic GHR protein levels were not detectable in both female and male aHepGHRkd mice, females maintained moderate levels of IGF1 and were protected from steatosis. The mechanism by which female mice are protected remains to be elucidated, however is consistent with clinical data indicating pre-menopausal women are resistance to NAFLD.

scholarly journals Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men

2020 ◽  
Vol 21 (11) ◽  
pp. 4144 ◽  
Author(s):  
Pia Fahlbusch ◽  
Birgit Knebel ◽  
Tina Hörbelt ◽  
David Monteiro Barbosa ◽  
Aleksandra Nikolic ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Energy Metabolism ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver

Fatty liver occurs from simple steatosis with accumulated hepatic lipids and hepatic insulin resistance to severe steatohepatitis, with aggravated lipid accumulation and systemic insulin resistance, but this progression is still poorly understood. Analyses of hepatic gene expression patterns from alb-SREBP-1c mice with moderate, or aP2-SREBP-1c mice with aggravated, hepatic lipid accumulation revealed IGFBP2 as key nodal molecule differing between moderate and aggravated fatty liver. Reduced IGFBP2 expression in aggravated fatty liver was paralleled with promoter hypermethylation, reduced hepatic IGFBP2 secretion and IGFBP2 circulating in plasma. Physiologically, the decrease of IGFBP2 was accompanied with reduced fatty acid oxidation and increased de novo lipogenesis potentially mediated by IGF1 in primary hepatocytes. Furthermore, methyltransferase and sirtuin activities were enhanced. In humans, IGFBP2 serum concentration was lower in obese men with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) compared to non-obese controls, and liver fat reduction by weight-loss intervention correlated with an increase of IGFBP2 serum levels. In conclusion, hepatic IGFBP2 abundance correlates to its circulating level and is related to hepatic energy metabolism and de novo lipogenesis. This designates IGFBP2 as non-invasive biomarker for fatty liver disease progression and might further provide an additional variable for risk prediction for pathogenesis of fatty liver in diabetes subtype clusters.

scholarly journals microRNA-99a Restricts Replication of Hepatitis C Virus by Targeting mTOR and De Novo Lipogenesis

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 696 ◽  
Author(s):  
Eun Byul Lee ◽  
Pil Soo Sung ◽  
Jung-Hee Kim ◽  
Dong Jun Park ◽  
Wonhee Hur ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Lipid Accumulation ◽  
De Novo ◽  
Regulatory Element ◽  
Mammalian Target Of Rapamycin ◽  
De Novo Lipogenesis ◽  
Hcv Rna ◽  
Intracellular Lipid ◽  
Intracellular Lipid Accumulation

In this study, we investigated the role of microRNA-99a (miR-99a) in hepatitis C virus (HCV) replication and lipogenesis in hepatocytes. Cell-culture-derived HCV (HCVcc) infection caused down-regulation of miR-99a in Huh-7 cells, and the relative levels of miR-99a were significantly lower in the sera of the HCV-infected patients than in those of healthy controls. Transfection of miR-99a-5p mimics resulted in a decrease in the intracellular and secreted HCV RNA levels. It also caused a decreased mammalian target of rapamycin (mTOR) protein level and phosphorylation of its downstream targets in HCV-replicating cells. Sterol regulatory element binding protein (SREBP)-1c expression and intracellular lipid accumulation decreased when either miR-99a-5p mimics or si-mTOR was transfected in oleic acid-treated Huh-7 cells. Overexpression of mTOR rescued HCV RNA replication and lipid droplet accumulation in miR-99a-5p mimics-transfected HCV replicon cells. Our data demonstrated that miR-99a ameliorates intracellular lipid accumulation by regulating mTOR/SREBP-1c and causes inefficient replication and packaging of intracellular HCV.

scholarly journals Niacin Ameliorates Hepatic Steatosis by Inhibiting De Novo Lipogenesis Via a GPR109A-Mediated PKC–ERK1/2–AMPK Signaling Pathway in C57BL/6 Mice Fed a High-Fat Diet

2019 ◽  
Vol 150 (4) ◽  
pp. 672-684 ◽  
Author(s):  
Lingyan Ye ◽  
Zheng Cao ◽  
Xiangru Lai ◽  
Ying Shi ◽  
Naiming Zhou
Keyword(s):  
Liver Disease ◽  
Protein Kinase ◽  
Fatty Liver ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Hepg2 Cells ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
High Fat

ABSTRACT Background Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Hepatic de novo lipogenesis (DNL) has been suggested to contribute to the pathogenesis of NAFLD. Recent studies have demonstrated that niacin (NA) modulates hepatic DNL through GPR109A. However, the underlying mechanism remains largely unknown. Objectives This study aims to elucidate the potential molecular mechanism by which GPR109A inhibits hepatic DNL. Methods C57BL/6 wild-type (WT) and Gpr109a knockout (KO) mice (male, 5 wk old) were fed a high-fat diet (60% energy from fat) firstly for 6 wk to generate a diet-induced obese model. Subsequently, they were randomly divided into 4 groups for the next 8–9 wk: WT mice with oral water [WT + vehile (VE)], WT mice with oral NA (50 mM, dissolved in water) (WT + NA), KO mice with oral water (KO + VE), and KO mice with oral NA (50 mM) (KO + NA). Mechanisms were examined in HepG2 cells. Body composition, liver histology, biomarkers of hepatic function, lipid accumulation, and lipid synthesis signals in HepG2 cells were measured. Results Upon activation, GPR109A apparently protected against obesity and hepatic steatosis (P < 0.05). The concentrations of hepatic Tnf-α in the WT + NA group were about 50% of those in the WT + VE group (P < 0.05). The activities of serum alanine transaminase and aspartate transaminase were 26.7% and 53.5% lower in the WT + NA group than in the WT + VE group, respectively (P < 0.05). In HepG2 cells, activation of GPR109A resulted in remarkable inhibition of oleic acid–induced lipid accumulation via a protein kinase C–extracellular signal-regulated kinase-1/2–AMP-activated protein kinase signaling pathway. Conclusions NA inhibits hepatic lipogenesis in C57BL/6 mice through a GPR109A-mediated signaling pathway, consistent with the mechanistic studies in HepG2 cells, suggesting its potential for treatment of NAFLD and other fatty liver diseases.

Targeting Ketohexokinase (KHK) with a Novel Antisense Oligonucleotide (ASO) Decreases De Novo Lipogenesis and Improves Insulin-Mediated Whole Body Glucose Metabolism

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 149-OR ◽  
Author(s):  
DONGQING LIU ◽  
JOHN A. STERPKA ◽  
DANIEL F. VATNER ◽  
MELANIE BELL ◽  
SUE MURRAY ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Antisense Oligonucleotide ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Whole Body

Model for measuring absolute rates of hepatic de novo lipogenesis and reesterification of free fatty acids

1993 ◽  
Vol 265 (5) ◽  
pp. E814-E820 ◽  
Author(s):  
M. K. Hellerstein ◽  
R. A. Neese ◽  
J. M. Schwarz
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
De Novo ◽  
Human Subjects ◽  
Fat Oxidation ◽  
De Novo Lipogenesis ◽  
Whole Body ◽  
Distribution Analysis ◽  
Oxidation Rates ◽  
Mass Isotopomer Distribution Analysis

We have previously presented a precursor-product stable isotopic technique for measuring in vivo the fraction of very low-density lipoprotein-fatty acids (VLDL-FA) derived from de novo lipogenesis (fractional DNL). Here, we propose a technique for converting fractional DNL into absolute rates of DNL and describe its explicit underlying assumptions. The technique combines the fractional DNL method with a modification of the method of S. Klein, V. R. Young, G. L. A. Blackburn, B. R. Bistrain, and R. R. Wolfe (J. Clin. Invest. 78: 928-933, 1986), for estimating hepatic reesterification of free fatty acids (FFA). Infusions of [1,2,3,4-13C]palmitate and [1-13C]acetate are performed concurrently with indirect calorimetry in human subjects. Fractional DNL (based on mass isotopomer distribution analysis of VLDL-FA), the rate of appearance of plasma FFA (Ra of FFA), and net fat oxidation in the whole body are measured. Equations from the hepatic reesterification model, modified to include the contribution from DNL, allow calculation of absolute DNL (= fractional DNL x [Ra of FFA - net whole body fat oxidation], when respiratory quotient < 1.0). Sample results from human subjects with different dietary energy intakes are presented, with calculations of absolute DNL, absolute reesterification, and absolute fat oxidation rates. The assumptions of this technique (in particular, that all fat oxidized is derived at steady state from circulating FFA and that DNL and reesterification of FFA both occur exclusively in liver) are discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

Sign in / Sign up

Export Citation Format

Share Document