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Article: Microbial functional pathways based on metatranscriptomic profiling enable effective saliva-based health assessments for precision wellness.

Patridge, Eric / Gorakshakar, Anmol / Molusky, Matthew M / Ogundijo, Oyetunji / Janevski, Angel / Julian, Cristina / Hu, Lan / Vuyisich, Momchilo / Banavar, Guruduth

Computational and structural biotechnology journal

2024 Volume 23, Page(s) 834–842

Abstract: It is increasingly recognized that an important step towards improving overall health is to accurately measure biomarkers of health from the molecular activities prevalent in the oral cavity. We present a general methodology for computationally ... ...

Abstract	It is increasingly recognized that an important step towards improving overall health is to accurately measure biomarkers of health from the molecular activities prevalent in the oral cavity. We present a general methodology for computationally quantifying the activity of microbial functional pathways using metatranscriptomic data. We describe their implementation as a collection of eight oral pathway scores using a large salivary sample dataset (n = 9350), and we evaluate score associations with oropharyngeal disease phenotypes within an unseen independent cohort (n = 14,129). Through this validation, we show that the relevant oral pathway scores are significantly worse in individuals with periodontal disease, acid reflux, and nicotine addiction, compared with controls. Given these associations, we make the case to use these oral pathway scores to provide molecular health insights from simple, non-invasive saliva samples, and as molecular endpoints for actionable interventions to address the associated conditions.
Language	English
Publishing date	2024-01-29
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2024.01.018
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Article ; Online: TTC39B destabilizes retinoblastoma protein promoting hepatic lipogenesis in a sex-specific fashion.

Hsieh, Joanne / Molusky, Matthew M / McCabe, Kristin M / Fotakis, Panagiotis / Xiao, Tong / Tascau, Liana / Zeana-Schliep, Lars / DaSilva-Jardine, Paul / Tall, Alan R

Journal of hepatology

2021 Volume 76, Issue 2, Page(s) 383–393

Abstract: Background & aims: Molecular mechanisms underlying the different susceptibility of men and women to non-alcoholic fatty liver disease (NAFLD) are poorly understood. The TTC39B locus encodes a scaffolding protein, associates with gynecological disorders ... ...

Abstract	Background & aims: Molecular mechanisms underlying the different susceptibility of men and women to non-alcoholic fatty liver disease (NAFLD) are poorly understood. The TTC39B locus encodes a scaffolding protein, associates with gynecological disorders and its deletion protects mice from diet-induced steatohepatitis. This study aimed to elucidate the molecular mechanisms linking TTC39B (T39) to the expression of lipogenic genes and to explore sex-specific effects. Methods: Co-expression in HEK293A cells validated the novel T39/pRb interaction predicted by a protein-protein interaction algorithm. T39 was knocked down using an antisense oligonucleotide (ASO) in mice with dietary NAFLD and a genetic deficiency of pRb or its downstream effector E2F1, as well as in primary human hepatocytes. Results: T39 interacts with pRb via its C-terminal TPR domain and promotes its proteasomal degradation. In female mice, T39 deficiency reduces the mRNA of lipogenic genes, especially Pnpla3, in a pRb- and E2F1-dependent manner. In contrast, in male mice, T39 deficiency results in a much smaller reduction in lipogenic gene expression that is independent of pRb/E2F1. T39 also interacts with VAPB via an N-terminal FFAT motif and stabilizes the interaction of VAPB with SCAP. Ovariectomy abolishes the effect of T39 knockdown on the hepatic pRb/E2F1/Pnpla3 axis. In both sexes T39 knockdown reduces SCAP independently of pRb. In primary human hepatocytes, T39 knockdown reduces expression of PNPLA3 and other lipogenic genes in women but not men. Conclusions: We have uncovered a conserved sexual dimorphism in the regulation of hepatic lipogenic genes, with effects of T39 mediated through pRb/E2F1 in females and VAPB/SCAP in both sexes. T39 inhibition could be a novel strategy to downregulate PNPLA3 and treat NAFLD in women. Lay summary: In females, the protein TTC39B degrades a tumor suppressor in the liver to promote the synthesis of new fat and the expression of a major genetic risk factor for non-alcoholic fatty liver disease. TTC39B is a potential therapeutic target for non-alcoholic fatty liver disease, especially in women.
MeSH term(s)	Animals ; Disease Models, Animal ; Gene Expression/genetics ; Gene Expression/physiology ; Lipogenesis/drug effects ; Lipogenesis/genetics ; Lipoproteins, HDL/adverse effects ; Mice ; Mice, Inbred C57BL/metabolism ; Neoplasm Proteins/adverse effects ; Retinoblastoma Protein/drug effects ; Sex Factors
Chemical Substances	Lipoproteins, HDL ; Neoplasm Proteins ; Retinoblastoma Protein ; TTC39B protein, human
Language	English
Publishing date	2021-09-30
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2021.09.021
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Article ; Online: Antisense oligonucleotide treatment produces a type I interferon response that protects against diet-induced obesity.

McCabe, Kristin M / Hsieh, Joanne / Thomas, David G / Molusky, Matthew M / Tascau, Liana / Feranil, Jun B / Qiang, Li / Ferrante, Anthony W / Tall, Alan R

Molecular metabolism

2020 Volume 34, Page(s) 146–156

Abstract: Objective: In mouse models, deficiency of TTC39B (T39) decreases hepatic lipogenic gene expression and protects against diet-induced steatohepatitis. While assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting T39, we ... ...

Abstract	Objective: In mouse models, deficiency of TTC39B (T39) decreases hepatic lipogenic gene expression and protects against diet-induced steatohepatitis. While assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting T39, we discovered an unexpected weight loss phenotype. The objective of this study was to determine the mechanism of the resistance to diet-induced obesity. Methods: To assess therapeutic potential, we used antisense oligonucleotides (ASO) to knock down T39 expression in a Western or high-fat, high-cholesterol, high-sucrose-diet-fed Ldlr Results: T39 ASO treatment led to decreased hepatic lipogenic gene expression and decreased hepatic triglycerides. Unexpectedly, T39 ASO treatment protected against diet-induced obesity. The reduced weight gain was seen with two different ASOs that decreased T39 mRNA in adipose tissue macrophages (ATMs), but not with a liver-targeted GalNac-ASO. Mice treated with the T39 ASO displayed increased browning of gonadal white adipose tissue (gWAT) and evidence of increased lipolysis. However, T39 knockout mice displayed a similar weight loss response when treated with T39 ASO, indicating an off-target effect. RNA-seq analysis of gWAT showed a widespread increase in type I interferon (IFN)-responsive genes, and knockout of the IFN receptor abolished the weight loss phenotype induced by the T39 ASO. Some human T39 ASOs and ASOs with different modifications targeting LDLR also induced a type I IFN response in THP1 macrophages. Conclusion: Our data suggest that extrahepatic targeting of T39 by ASOs in ATMs produced an off-target type 1 IFN response, leading to activation of lipolysis, browning of WAT, and weight loss. While our findings suggest that ASOs may induce off-target type 1 IFN response more commonly than previously thought, they also suggest that therapeutic induction of type 1 IFN selectively in ATMs could potentially represent a novel approach to the treatment of obesity.
MeSH term(s)	Animals ; Diet, High-Fat/adverse effects ; Female ; Injections, Subcutaneous ; Interferon Type I/biosynthesis ; Interferon Type I/deficiency ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Obesity/chemically induced ; Obesity/drug therapy ; Obesity/metabolism ; Obesity/prevention & control ; Oligonucleotides, Antisense/administration & dosage ; Oligonucleotides, Antisense/pharmacology
Chemical Substances	Interferon Type I ; Oligonucleotides, Antisense
Language	English
Publishing date	2020-01-30
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2020.01.010
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Article ; Online: Metformin and AMP Kinase Activation Increase Expression of the Sterol Transporters ABCG5/8 (ATP-Binding Cassette Transporter G5/G8) With Potential Antiatherogenic Consequences.

Molusky, Matthew M / Hsieh, Joanne / Lee, Samuel X / Ramakrishnan, Rajasekhar / Tascau, Liana / Haeusler, Rebecca A / Accili, Domenico / Tall, Alan R

Arteriosclerosis, thrombosis, and vascular biology

2018 Volume 38, Issue 7, Page(s) 1493–1503

Abstract: Objective: The mechanisms underlying the cardiovascular benefit of the anti-diabetic drug metformin are poorly understood. Recent studies have suggested metformin may upregulate macrophage reverse cholesterol transport. The final steps of reverse ... ...

Abstract	Objective: The mechanisms underlying the cardiovascular benefit of the anti-diabetic drug metformin are poorly understood. Recent studies have suggested metformin may upregulate macrophage reverse cholesterol transport. The final steps of reverse cholesterol transport are mediated by the sterol transporters, ABCG5 (ATP-binding cassette transporter G5) and ABCG8 (ATP-binding cassette transporter G8), which facilitate hepato-biliary transport of cholesterol. This study was undertaken to assess the possibility that metformin induces Approach and results: Metformin-treated mouse or human primary hepatocytes showed increased expression of Conclusions: Our findings provide partial support for the concept that metformin may provide cardiovascular benefit via increased reverse cholesterol transport but also indicate increased
MeSH term(s)	AMP-Activated Protein Kinases/deficiency ; AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 5/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 8/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 8/metabolism ; ATP Citrate (pro-S)-Lyase/metabolism ; Animals ; Cholesterol/blood ; Enzyme Activation ; HEK293 Cells ; Hepatocytes/drug effects ; Hepatocytes/enzymology ; Humans ; Lipoproteins/genetics ; Lipoproteins/metabolism ; Male ; Metformin/pharmacology ; Mice, Inbred C57BL ; Mice, Knockout ; Period Circadian Proteins/metabolism ; Primary Cell Culture ; Receptors, LDL/metabolism ; Up-Regulation
Chemical Substances	ABCG5 protein, human ; ABCG5 protein, mouse ; ABCG8 protein, human ; ABCG8 protein, mouse ; ATP Binding Cassette Transporter, Subfamily B, Member 11 ; ATP Binding Cassette Transporter, Subfamily G, Member 5 ; ATP Binding Cassette Transporter, Subfamily G, Member 8 ; Abcb11 protein, mouse ; Lipoproteins ; Per2 protein, mouse ; Period Circadian Proteins ; Receptors, LDL ; Metformin (9100L32L2N) ; Cholesterol (97C5T2UQ7J) ; ATP Citrate (pro-S)-Lyase (EC 2.3.3.8) ; AMPK alpha1 subunit, mouse (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; PRKAA1 protein, human (EC 2.7.11.31)
Language	English
Publishing date	2018-05-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.118.311212
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Article ; Online: Circadian autophagy rhythm: a link between clock and metabolism?

Ma, Di / Li, Siming / Molusky, Matthew M / Lin, Jiandie D

Trends in endocrinology and metabolism: TEM

2012 Volume 23, Issue 7, Page(s) 319–325

Abstract: Nutrient and energy metabolism in mammals exhibits a strong diurnal rhythm that aligns with the body clock. Circadian regulation of metabolism is mediated through reciprocal signaling between the clock and metabolic regulatory networks. Recent work has ... ...

Abstract	Nutrient and energy metabolism in mammals exhibits a strong diurnal rhythm that aligns with the body clock. Circadian regulation of metabolism is mediated through reciprocal signaling between the clock and metabolic regulatory networks. Recent work has demonstrated that autophagy is rhythmically activated in a clock-dependent manner. Because autophagy is a conserved biological process that contributes to nutrient and cellular homeostasis, its cyclic induction may provide a novel link between clock and metabolism. This review discusses the mechanisms underlying circadian autophagy regulation, the role of rhythmic autophagy in nutrient and energy metabolism, and its implications in physiology and metabolic disease.
MeSH term(s)	Animals ; Autophagy/physiology ; Circadian Rhythm/physiology ; Energy Metabolism/physiology ; Humans ; Metabolic Networks and Pathways
Language	English
Publishing date	2012-04-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1042384-9
ISSN	1879-3061 ; 1043-2760
ISSN (online)	1879-3061
ISSN	1043-2760
DOI	10.1016/j.tem.2012.03.004
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Zs.A 2999: Show issues

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Article ; Online: Anti-Inflammatory Effects of HDL (High-Density Lipoprotein) in Macrophages Predominate Over Proinflammatory Effects in Atherosclerotic Plaques.

Fotakis, Panagiotis / Kothari, Vishal / Thomas, David G / Westerterp, Marit / Molusky, Matthew M / Altin, Elissa / Abramowicz, Sandra / Wang, Nan / He, Yi / Heinecke, Jay W / Bornfeldt, Karin E / Tall, Alan R

Arteriosclerosis, thrombosis, and vascular biology

2019 Volume 39, Issue 12, Page(s) e253–e272

Abstract: Objective: HDL (high-density lipoprotein) infusion reduces atherosclerosis in animal models and is being evaluated as a treatment in humans. Studies have shown either anti- or proinflammatory effects of HDL in macrophages, and there is no consensus on ... ...

Abstract	Objective: HDL (high-density lipoprotein) infusion reduces atherosclerosis in animal models and is being evaluated as a treatment in humans. Studies have shown either anti- or proinflammatory effects of HDL in macrophages, and there is no consensus on the underlying mechanisms. Here, we interrogate the effects of HDL on inflammatory gene expression in macrophages. Approach and Results: We cultured bone marrow-derived macrophages, treated them with reconstituted HDL or HDL isolated from Conclusions: Reconstituted HDL infusions in hypercholesterolemic atherosclerotic mice produced anti-inflammatory effects in lesion macrophages suggesting a beneficial therapeutic effect of HDL in vivo.
MeSH term(s)	Animals ; Aorta, Thoracic/metabolism ; Aorta, Thoracic/pathology ; Carrier Proteins/biosynthesis ; Carrier Proteins/genetics ; Cells, Cultured ; Disease Models, Animal ; Female ; Flow Cytometry ; Gene Expression Regulation ; Immunoblotting ; Inflammation/genetics ; Inflammation/metabolism ; Inflammation/pathology ; Lipoproteins, HDL/pharmacology ; Macrophages/metabolism ; Macrophages/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Plaque, Atherosclerotic/genetics ; Plaque, Atherosclerotic/metabolism ; Plaque, Atherosclerotic/pathology ; Recombinant Proteins
Chemical Substances	Carrier Proteins ; Lipoproteins, HDL ; Recombinant Proteins ; TLR4-associated protein, mouse
Language	English
Publishing date	2019-10-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.119.313253
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Article ; Online: Antisense oligonucleotide treatment produces a type I interferon response that protects against diet-induced obesity

Kristin M. McCabe / Joanne Hsieh / David G. Thomas / Matthew M. Molusky / Liana Tascau / Jun B. Feranil / Li Qiang / Anthony W. Ferrante, Jr. / Alan R. Tall

Molecular Metabolism, Vol 34, Iss , Pp 146-

2020 Volume 156

Abstract	Objective: In mouse models, deficiency of TTC39B (T39) decreases hepatic lipogenic gene expression and protects against diet-induced steatohepatitis. While assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting T39, we discovered an unexpected weight loss phenotype. The objective of this study was to determine the mechanism of the resistance to diet-induced obesity. Methods: To assess therapeutic potential, we used antisense oligonucleotides (ASO) to knock down T39 expression in a Western or high-fat, high-cholesterol, high-sucrose-diet-fed Ldlr−/− or wild-type mice. Results: T39 ASO treatment led to decreased hepatic lipogenic gene expression and decreased hepatic triglycerides. Unexpectedly, T39 ASO treatment protected against diet-induced obesity. The reduced weight gain was seen with two different ASOs that decreased T39 mRNA in adipose tissue macrophages (ATMs), but not with a liver-targeted GalNac-ASO. Mice treated with the T39 ASO displayed increased browning of gonadal white adipose tissue (gWAT) and evidence of increased lipolysis. However, T39 knockout mice displayed a similar weight loss response when treated with T39 ASO, indicating an off-target effect. RNA-seq analysis of gWAT showed a widespread increase in type I interferon (IFN)-responsive genes, and knockout of the IFN receptor abolished the weight loss phenotype induced by the T39 ASO. Some human T39 ASOs and ASOs with different modifications targeting LDLR also induced a type I IFN response in THP1 macrophages. Conclusion: Our data suggest that extrahepatic targeting of T39 by ASOs in ATMs produced an off-target type 1 IFN response, leading to activation of lipolysis, browning of WAT, and weight loss. While our findings suggest that ASOs may induce off-target type 1 IFN response more commonly than previously thought, they also suggest that therapeutic induction of type 1 IFN selectively in ATMs could potentially represent a novel approach to the treatment of obesity. Keywords: Obesity, White adipose tissue, Type I interferon, Antisense oligonucleotides, Adipose tissue macrophages
Keywords	Internal medicine ; RC31-1245
Subject code	616
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Peroxisomal localization and circadian regulation of ubiquitin-specific protease 2.

Molusky, Matthew M / Ma, Di / Buelow, Katie / Yin, Lei / Lin, Jiandie D

PloS one

2012 Volume 7, Issue 11, Page(s) e47970

Abstract: Temporal regulation of nutrient and energy metabolism is emerging as an important aspect of metabolic homeostasis. The regulatory network that integrates the timing cues and nutritional signals to drive diurnal metabolic rhythms remains poorly defined. ... ...

Abstract	Temporal regulation of nutrient and energy metabolism is emerging as an important aspect of metabolic homeostasis. The regulatory network that integrates the timing cues and nutritional signals to drive diurnal metabolic rhythms remains poorly defined. The 45-kDa isoform of ubiquitin-specific protease 2 (USP2-45) is a deubiquitinase that regulates hepatic gluconeogenesis and glucose metabolism. In this study, we found that USP2-45 is localized to peroxisomes in hepatocytes through a canonical peroxisome-targeting motif at its C-terminus. Clustering analysis indicates that the expression of a subset of peroxisomal genes exhibits robust diurnal rhythm in the liver. Despite this, nuclear hormone receptor PPARα, a known regulator of peroxisome gene expression, does not induce USP2-45 in hepatocytes and is dispensible for its expression during starvation. In contrast, a functional liver clock is required for the proper nutritional and circadian regulation of USP2-45 expression. At the molecular level, transcriptional coactivators PGC-1α and PGC-1β and repressor E4BP4 exert opposing effects on USP2-45 promoter activity. These studies provide insights into the subcellular localization and transcriptional regulation of a clock-controlled deubiquitinase that regulates glucose metabolism.
MeSH term(s)	Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Basic-Leucine Zipper Transcription Factors/biosynthesis ; Circadian Rhythm ; Endopeptidases/metabolism ; Gene Expression Regulation ; Glucose/metabolism ; Hepatocytes/cytology ; Mice ; Mice, Inbred C57BL ; Models, Biological ; Molecular Sequence Data ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Peroxisomes/metabolism ; Promoter Regions, Genetic ; Protein Isoforms ; Protein Structure, Tertiary ; Trans-Activators/biosynthesis ; Transcription Factors ; Ubiquitin Thiolesterase ; Ubiquitin-Specific Proteases
Chemical Substances	Basic-Leucine Zipper Transcription Factors ; Nfil3 protein, mouse ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Ppargc1a protein, mouse ; Protein Isoforms ; Trans-Activators ; Transcription Factors ; Endopeptidases (EC 3.4.-) ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Ubiquitin-Specific Proteases (EC 3.4.19.12) ; Usp2 protein, mouse (EC 3.4.19.12) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2012-11-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0047970
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Article ; Online: Ubiquitin-specific protease 2 regulates hepatic gluconeogenesis and diurnal glucose metabolism through 11β-hydroxysteroid dehydrogenase 1.

Molusky, Matthew M / Li, Siming / Ma, Di / Yu, Lei / Lin, Jiandie D

Diabetes

2012 Volume 61, Issue 5, Page(s) 1025–1035

Abstract: Hepatic gluconeogenesis is important for maintaining steady blood glucose levels during starvation and through light/dark cycles. The regulatory network that transduces hormonal and circadian signals serves to integrate these physiological cues and ... ...

Abstract	Hepatic gluconeogenesis is important for maintaining steady blood glucose levels during starvation and through light/dark cycles. The regulatory network that transduces hormonal and circadian signals serves to integrate these physiological cues and adjust glucose synthesis and secretion by the liver. In this study, we identified ubiquitin-specific protease 2 (USP2) as an inducible regulator of hepatic gluconeogenesis that responds to nutritional status and clock. Adenoviral-mediated expression of USP2 in the liver promotes hepatic glucose production and exacerbates glucose intolerance in diet-induced obese mice. In contrast, in vivo RNA interference (RNAi) knockdown of this factor improves systemic glycemic control. USP2 is a target gene of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a coactivator that integrates clock and energy metabolism, and is required for maintaining diurnal glucose homeostasis during restricted feeding. At the mechanistic level, USP2 regulates hepatic glucose metabolism through its induction of 11β-hydroxysteroid dehydrogenase 1 (HSD1) and glucocorticoid signaling in the liver. Pharmacological inhibition and liver-specific RNAi knockdown of HSD1 significantly impair the stimulation of hepatic gluconeogenesis by USP2. Together, these studies delineate a novel pathway that links hormonal and circadian signals to gluconeogenesis and glucose homeostasis.
MeSH term(s)	11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics ; 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism ; Adipose Tissue, White/metabolism ; Animals ; Cells, Cultured ; Circadian Rhythm ; Endopeptidases/genetics ; Endopeptidases/metabolism ; Food Deprivation ; Gene Expression Regulation, Enzymologic ; Gluconeogenesis/physiology ; Glucose/metabolism ; Hepatocytes/cytology ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Insulin/metabolism ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal/metabolism ; Polymerase Chain Reaction ; RNA Interference ; RNA, Messenger/metabolism ; Signal Transduction ; Ubiquitin Thiolesterase ; Ubiquitin-Specific Proteases
Chemical Substances	Insulin ; RNA, Messenger ; 11-beta-Hydroxysteroid Dehydrogenase Type 1 (EC 1.1.1.146) ; Endopeptidases (EC 3.4.-) ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Ubiquitin-Specific Proteases (EC 3.4.19.12) ; Usp2 protein, mouse (EC 3.4.19.12) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2012-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db11-0970
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Article ; Online: Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity.

Westerterp, Marit / Gautier, Emmanuel L / Ganda, Anjali / Molusky, Matthew M / Wang, Wei / Fotakis, Panagiotis / Wang, Nan / Randolph, Gwendalyn J / D'Agati, Vivette D / Yvan-Charvet, Laurent / Tall, Alan R

Cell metabolism

2017 Volume 25, Issue 6, Page(s) 1294–1304.e6

Abstract: Autoimmune diseases such as systemic lupus erythematosus (SLE) are associated with increased cardiovascular disease and reduced plasma high-density lipoprotein (HDL) levels. HDL mediates cholesterol efflux from immune cells via the ATP binding cassette ... ...

Abstract	Autoimmune diseases such as systemic lupus erythematosus (SLE) are associated with increased cardiovascular disease and reduced plasma high-density lipoprotein (HDL) levels. HDL mediates cholesterol efflux from immune cells via the ATP binding cassette transporters A1 and G1 (ABCA1/G1). The significance of impaired cholesterol efflux pathways in autoimmunity is unknown. We observed that Abca1/g1-deficient mice develop enlarged lymph nodes (LNs) and glomerulonephritis suggestive of SLE. This lupus-like phenotype was recapitulated in mice with knockouts of Abca1/g1 in dendritic cells (DCs), but not in macrophages or T cells. DC-Abca1/g1 deficiency increased LN and splenic CD11b
MeSH term(s)	ATP Binding Cassette Transporter 1/genetics ; ATP Binding Cassette Transporter 1/immunology ; ATP Binding Cassette Transporter, Subfamily G, Member 1/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 1/immunology ; Adaptive Immunity ; Animals ; Cholesterol/genetics ; Cholesterol/immunology ; Dendritic Cells/immunology ; Immune Tolerance ; Inflammasomes/genetics ; Inflammasomes/immunology ; Mice ; Mice, Knockout ; Th1 Cells/immunology ; Th17 Cells/immunology
Chemical Substances	ABCA1 protein, mouse ; ABCG1 protein, mouse ; ATP Binding Cassette Transporter 1 ; ATP Binding Cassette Transporter, Subfamily G, Member 1 ; Inflammasomes ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2017-05-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2017.04.005
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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