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.

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 HFD-induced hepatic lipid accumulation and inflammation are decreased in Factor D deficient mouse

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hiromi Tsuru ◽  
Mizuko Osaka ◽  
Yuichi Hiraoka ◽  
Masayuki Yoshida
Keyword(s):  
Lipid Accumulation ◽  
De Novo ◽  
Fatty Acid Uptake ◽  
De Novo Lipogenesis ◽  
Inflammatory Factors ◽  
Acid Uptake ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Expression Of Genes

Abstract Excessive intake of fat causes accumulation of fat in liver, leading to non-alcoholic fatty liver disease (NAFLD). High-fat diet (HFD) upregulates the expression of Factor D, a complement pathway component, in the liver of mice. However, the functions of Factor D in liver are not well known. Therefore, the current study investigated the relationship between Factor D and hepatic lipid accumulation using CRISPR/Cas9-mediated Factor D knockout (FD-KO) mice. Factor D deficiency downregulated expression of genes related to fatty acid uptake and de novo lipogenesis in the liver. Furthermore, Factor D deficiency reduced the expression of inflammatory factors (Tnf and Ccl2) and fibrosis markers and decreased accumulation of F4/80-positive macrophages. These data suggest that the Factor D deficiency improved hepatic lipid accumulation and hepatic inflammation in HFD-fed mice.

scholarly journals mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
C. Martinez Calejman ◽  
S. Trefely ◽  
S. W. Entwisle ◽  
A. Luciano ◽  
S. M. Jung ◽  
...  
Keyword(s):  
De Novo ◽  
Ppar Gamma ◽  
Akt Signaling ◽  
De Novo Lipogenesis ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Brown Adipocytes ◽  
Glucose And Lipid Metabolism ◽  
Citrate Lyase ◽  
Acetyl Coa Synthesis

Abstract mTORC2 phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In brown adipocytes, mTORC2 regulates glucose and lipid metabolism, however the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate in brown preadipocytes. mTORC2 appears dispensable for most other AKT actions examined, indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments suggest brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. Evidence in mature brown adipocytes also suggests mTORC2 acts through ACLY to increase carbohydrate response element binding protein (ChREBP) activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis.

scholarly journals mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (18) ◽  
pp. 25224-25240 ◽  
Author(s):  
Yaqing Chen ◽  
Jianchang Qian ◽  
Qun He ◽  
Hui Zhao ◽  
Lourdes Toral-Barza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase

scholarly journals Rottlerin Suppresses Fat Accumulation by Inhibiting Adipogenesis and De Novo Lipogenesis in 3T3-L1 Adipocytes

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1224-1224
Author(s):  
Ye Jin Kim ◽  
Gwang-woong !Go
Keyword(s):  
Lipid Accumulation ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Dependent Manner ◽  
Gene Expressions ◽  
Alcoholic Fatty Liver ◽  
Protein Levels ◽  
Funding Sources ◽  
Mrna Gene ◽  
Oil Red O

Abstract Objectives Rottlerin is isolated from Mallotus japonicus, a rich-in polyphenol. Rottlerin is a PKC delta inhibitor known for an uncoupler of oxidative phosphorylation and anti-neoplastic agent. However, the effect of anti-obesity is not conclusive. This study hypothesized that rottlerin inhibits lipid accumulation in adipocytes. Methods 3T3-L1 cells were maintained with DMEM containing 10% BCS and 1% penicillin. The cells were seeded in a 6-well plate with a density of 8 × 104 followed by cultured for 4 days until reaching 120% confluency and incubated in a differentiation medium for 6 days. Rottlerin was incubated with differentiation media (0, 1, 2, and 4 µM). Cells were harvested after treatment for measurement of Oil Red O stating, immunoblotting, and RT-PCR. Results Differentiated 3T3-L1 adipocytes were stained using the Oil Red O, which stains triglycerides into the red. Lipid accumulation was significantly inhibited in 4 µM of rottlerin (P < 0.001). In protein levels, PPARγ, an adipogenesis marker, was reduced dose-dependently decreased (P < 0.001), indicating lipid droplet formation reduced. FAS and SCD1 were diminished by rottlerin treated groups (all P < 0.001). ACC-pS79/ACC was increased by rottlerin (P = 0.02). In mRNA gene expressions, C/EBPα was reduced by rottlerin in a dose-dependent manner (P < 0.001), and PPARγ tend to be decreased by rottlerin (P = 0.06). FAS and SREBP1 were inhibited by rottlerin (P < 0.01). SCD1 was dramatically reduced by rottlerin (P < 0.001). Conclusions We found that rottlerin reduces lipid accumulation by inhibiting adipogenesis in differentiated 3T3-L1 adipocytes. This suggests that rottlerin is a potential nutraceutical for treating dyslipidemia, non-alcoholic fatty liver disease, and obesity. Funding Sources This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT; MSIT).

scholarly journals Author Correction: mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
C. Martinez Calejman ◽  
S. Trefely ◽  
S. W. Entwisle ◽  
A. Luciano ◽  
S. M. Jung ◽  
...  
Keyword(s):  
De Novo ◽  
Akt Signaling ◽  
De Novo Lipogenesis ◽  
Atp Citrate Lyase ◽  
Citrate Lyase ◽  
Brown Adipogenesis

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals A Narrative Review on the Role of AMPK on De Novo Lipogenesis in Non-Alcoholic Fatty Liver Disease: Evidence from Human Studies

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1822
Author(s):  
Christian von Loeffelholz ◽  
Sina M. Coldewey ◽  
Andreas L. Birkenfeld
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Mammalian Cells ◽  
De Novo ◽  
Adenosine Monophosphate ◽  
De Novo Lipogenesis ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

5′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of essential molecular pathways. By phosphorylation of downstream proteins and modulation of gene transcription AMPK functions as a master switch of energy homeostasis in tissues with high metabolic turnover, such as the liver, skeletal muscle, and adipose tissue. Regulation of AMPK under conditions of chronic caloric oversupply emerged as substantial research target to get deeper insight into the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Evidence supporting the role of AMPK in NAFLD is mainly derived from preclinical cell culture and animal studies. Dysbalanced de novo lipogenesis has been identified as one of the key processes in NAFLD pathogenesis. Thus, the scope of this review is to provide an integrative overview of evidence, in particular from clinical studies and human samples, on the role of AMPK in the regulation of primarily de novo lipogenesis in human NAFLD.

scholarly journals Hepatic GH Receptor Signaling Directly Suppresses Hepatic Steatosis and De Novo Lipogenesis, Independent of Changes in Plasma IGF1 and Insulin

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A48-A48
Author(s):  
Maria del Carmen Vazquez Borrego ◽  
Mercedes del Rio Moreno ◽  
Andre Sarmento-Cabral ◽  
Mariyah Mahmood ◽  
Papasani V Subbaiah ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Target Genes ◽  
De Novo ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Mrna Levels ◽  
Male Mice ◽  
Alcoholic Fatty Liver ◽  
Insulin Levels ◽  
Triglyceride Accumulation

Abstract A reduction in GH, as well as IGF1, is associated with non-alcoholic fatty liver disease (NAFLD). However, the relative contribution of changes in circulating GH and IGF1, to hepatic triglyceride accumulation (steatosis), remains to be clearly defined. To study the direct actions of GH on hepatocyte metabolism, we have utilized a mouse model of adult-onset, hepatocyte-specific, GHR knockdown (aHepGHRkd; 10–12 week-old, GHRfl/fl male mice, treated with AAV8-TBGp-Cre). In this and previous reports, we have observed that aHepGHRkd male mice rapidly develop steatosis (after 7 days) associated with enhanced de novo lipogenesis (DNL; measured by deuterated H2O labeling, 10h after 0800h food removal), and low ketone levels, suggestive of reduced hepatic β-oxidation. Of note, aHepGHRkd also reduces plasma IGF1 levels to >80% of GHR-intact controls (GHRfl/fl mice treated with AAV8-TBGp-Null), leading to a rise in GH, due to loss of IGF1 negative feedback to the pituitary/hypothalamus. This reciprocal shift in IGF1/GH is associated with an increase in insulin levels. Therefore, it is possible that the steatosis that develops in aHepGHRkd mice is the consequence of systemic insulin resistance supplying excess substrates (glucose and NEFA) for hepatic lipogenesis. However, inconsistent with this theory is the fact that glucose and NEFA levels are not altered after aHepGHRkd. To tease out the indirect (perhaps driven by high insulin levels) vs. direct effects of GH on hepatocyte lipid accumulation, male aHepGHRkd mice were injected with a vector expressing rat IGF1 (AAV8-TBGp-rIGF1). Reconstitution of hepatocyte IGF1 in aHepGHRkd mice, raised plasma IGF1 and normalized GH, insulin and ketone levels, but hepatic steatosis and DNL remained greater than that of GHR-intact controls, indicating GH directly suppresses hepatic fat accumulation. RNAseq analysis of livers from aHepGHRkd mice showed expression of genes related to carbohydrate metabolism (Gck, Khk) and fatty acid synthesis (Fasn, Srebf1, Usf1), processing (Scd1) and uptake (Cd36) were increased, while genes related to gluconeogenesis (Pck1, Fbp1, G6pc) were reduced. Remarkably, IGF1 reconstitution had no major impact on the hepatic transcriptome of aHepGHRkd mice, with the exception of reducing the expression of Srebf1, consistent with the reduction in circulating insulin levels. Interestingly, carbohydrate-responsive element-binding protein (CHREBP) levels, but not mRNA levels, were greater in aHepGHRkd mice with or without IGF1 reconstitution, consistent with upregulation of CHREBP target genes (Khk and Fasn among others). Taken together, these results suggest GH directly regulates steatosis, at least in part, by suppressing carbohydrate-driven DNL, where additional studies are underway to test this hypothesis.

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