Transcriptomic Analysis Reveals a Sex-Dimorphic Influence of GAT-2 on Murine Liver Function

Accumulating evidence shows that the γ-amino butyric acid (GABA)ergic system affects the functions of different organs, and liver is one of the most sex-dimorphic organs in animals. However, whether and how the GABAergic system influences liver function in a sex-specific manner at the intrinsic molecular level remains elusive. In this study, firstly, we find that the levels of GABA are significantly increased in the livers of female mice with GABA transporter (GAT)-2 deficiency (KO) whereas it only slightly increased in male GAT-2 KO mice. Apart from the amino acid profiles, the expressions of toll-like receptors (TLRs) also differ in the livers of female and male KO mice. Moreover, RNA-seq results show 2,227 differentially expressed genes (DEGs) in which 1,030 are upregulated whereas 1,197 that are downregulated in the livers of female KO mice. Notably, oxidative phosphorylation, non-alcoholic fatty liver disease, Huntington's disease, and peroxisome proliferator-activated receptor (PPAR) signaling pathways are highly enriched by GAT-2 deficiency, indicating that these pathways probably meditate the effects of GAT-2 on female liver functions, on the other hand, only 1,233 DEGs, including 474 are upregulated and 759 are downregulated in the livers of male KO mice. Interestingly, retinol metabolism, PPAR signaling pathway, and tuberculosis pathways are substantially enriched by GAT-2 deficiency, suggesting that these pathways may be responsible for the effects of GAT-2 on male liver functions. Collectively, our results reveal the sex-dimorphic effects of GAT-2 in guiding liver functions, and we propose that targeting the GABAergic system (e.g., GATs) in a sex-specific manner could provide previously unidentified therapeutic opportunities for liver diseases.

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Signaling and other functions of lipids in autophagy: a review

Lipids in Health and Disease ◽

10.1186/s12944-020-01389-2 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Alejandro Soto-Avellaneda ◽

Brad E. Morrison

Keyword(s):

Signaling Pathways ◽

Mammalian Target Of Rapamycin ◽

Lipid Vesicle ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Alcoholic Fatty Liver ◽

Muscular Disorders ◽

Ppar Signaling ◽

Lipid Compounds

Abstract The process of autophagy is integral to cellular function. In this process, proteins, organelles, and metabolites are engulfed in a lipid vesicle and trafficked to a lysosome for degradation. Its central role in protein and organelle homeostasis has piqued interest for autophagy dysfunction as a driver of pathology for a number of diseases including cancer, muscular disorders, neurological disorders, and non-alcoholic fatty liver disease. For much of its history, the study of autophagy has centered around proteins, however, due to advances in mass spectrometry and refined methodologies, the role of lipids in this essential cellular process has become more apparent. This review discusses the diverse endogenous lipid compounds shown to mediate autophagy. Downstream lipid signaling pathways are also reviewed in the context of autophagy regulation. Specific focus is placed upon the Mammalian Target of Rapamycin (mTOR) and Peroxisome Proliferator-Activated Receptor (PPAR) signaling pathways as integration hubs for lipid regulation of autophagy.

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Natural Aldose Reductase Inhibitor: A Potential Therapeutic Agent for Non-alcoholic Fatty Liver Disease

Current Drug Targets ◽

10.2174/1389450120666191007111712 ◽

2020 ◽

Vol 21 (6) ◽

pp. 599-609 ◽

Cited By ~ 3

Author(s):

Longxin Qiu ◽

Chang Guo

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Fatty Liver ◽

Aldose Reductase ◽

Fatty Liver Disease ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Alcoholic Fatty Liver ◽

Nonalcoholic Fatty Liver

Aldose reductase (AR) has been reported to be involved in the development of nonalcoholic fatty liver disease (NAFLD). Hepatic AR is induced under hyperglycemia condition and converts excess glucose to lipogenic fructose, which contributes in part to the accumulation of fat in the liver cells of diabetes rodents. In addition, the hyperglycemia-induced AR or nutrition-induced AR causes suppression of the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) α and reduced lipolysis in the liver, which also contribute to the development of NAFLD. Moreover, AR induction in non-alcoholic steatohepatitis (NASH) may aggravate oxidative stress and the expression of inflammatory cytokines in the liver. Here, we summarize the knowledge on AR inhibitors of plant origin and review the effect of some plant-derived AR inhibitors on NAFLD/NASH in rodents. Natural AR inhibitors may improve NAFLD at least in part through attenuating oxidative stress and inflammatory cytokine expression. Some of the natural AR inhibitors have been reported to attenuate hepatic steatosis through the regulation of PPARα-mediated fatty acid oxidation. In this review, we propose that the natural AR inhibitors are potential therapeutic agents for NAFLD.

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Influence of irisin on diet-induced metabolic syndrome in experimental rat model

Journal of Complementary and Integrative Medicine ◽

10.1515/jcim-2020-0030 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Dalia Medhat ◽

Mona A. El-Bana ◽

Sherien M. El-Daly ◽

Magdi N. Ashour ◽

Tahany R. Elias ◽

...

Keyword(s):

Skeletal Muscle ◽

Lipid Profile ◽

Histopathological Examination ◽

Retinol Binding Protein ◽

Albino Rats ◽

Standard Diet ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Alcoholic Fatty Liver ◽

Kidney Functions

Abstract Objective To evaluate the influence of irisin on the experimental paradigm of non-alcoholic fatty liver (NAFL) as a part of MetS cluster. Methods Forty male albino rats were divided into four groups; normal control, standard diet + irisin, high carbohydrate and fat diet (HCHF), and HCHF + irisin. After the experimental period, levels of fasting blood sugar (FBS), insulin, lipid profile, kidney functions, salusin-alpha (Sal-α), adropin, and retinol-binding protein-4 (RBP-4) were evaluated. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) expression in skeletal muscle was evaluated by quantitative real-time PCR. Aorta, liver, pancreas, and skeletal muscle tissue samples were prepared for histopathological examination. Results Rats administrated HCHF showed elevated levels of FBS, lipid profile, kidney functions, RBP-4, and downregulation of PGC-1α expression along with a decline in levels of insulin, Sal-α, and adropin while administration of irisin significantly attenuated these levels. Conclusions Irisin as based therapy could emerge as a new line of treatment against MetS and its related diseases.

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Physiologic and Pharmacologic Modulation of Glucose-Dependent Insulinotropic Polypeptide (GIP) Receptor Expression in -Cells by Peroxisome Proliferator-Activated Receptor (PPAR)- Signaling: Possible Mechanism for the GIP Resistance in Type 2 Diabetes

Diabetes ◽

10.2337/db09-1655 ◽

2010 ◽

Vol 59 (6) ◽

pp. 1445-1450 ◽

Cited By ~ 34

Author(s):

D. Gupta ◽

M. Peshavaria ◽

N. Monga ◽

T. L. Jetton ◽

J. L. Leahy

Keyword(s):

Type 2 Diabetes ◽

Receptor Expression ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Signaling ◽

Pharmacologic Modulation ◽

Gip Receptor ◽

In Cells

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Abstract 290: Proliferation of Cardiac Fibroblasts Defines Early Stages of Genetic Dilated Cardiomyopathy and Precedes Myocardial Metabolic Derangement

Circulation Research ◽

10.1161/res.115.suppl_1.290 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Michael A Burke ◽

Stephen Chang ◽

Danos C Christodoulou ◽

Joshua M Gorham ◽

Hiroko Wakimoto ◽

...

Keyword(s):

Gene Expression ◽

Cardiac Fibroblasts ◽

Expression Patterns ◽

Molecular Networks ◽

Peroxisome Proliferator ◽

Metabolic Derangement ◽

Peroxisome Proliferator Activated Receptor ◽

Cell Remodeling ◽

Ppar Signaling ◽

Myocyte Proliferation

The complex molecular networks underpinning DCM remain poorly understood. To study distinct pathways and networks in the longitudinal development of DCM we performed RNAseq on LV tissue from mice carrying a human DCM mutation in phospholamban (PLN R9C/+ ) before phenotype onset (pre-DCM), with DCM, and during overt heart failure (HF), and also on isolated myocytes and non-myocytes from DCM hearts. PLN R9C/+ mice show progressive fibrosis (20% vs. 1% control, p=6x10 −33 ; n=3) associated with proliferation of cardiac non-myocytes (33% increase over control, p=6x10 −4 ; n=3). Consistent with this, cardiac non-myocytes have upregulated gene expression and pathways, while these are generally downregulated in myocytes. Non-myocytes were enriched in fibrosis, inflammation, and cell remodeling pathways, from pre-DCM to HF. In contrast, myocytes were enriched for metabolic pathways only with overt DCM and HF. Myocytes showed profound derangement of oxidative phosphorylation with DCM (p=2.5x10 −41 ; 44% (53/120) of pathway genes downregulated), suggesting mitochondrial dysfunction. Additionally, we detected probable inhibition of peroxisome proliferator-activated receptor (PPAR) signaling by diminished expression of pathway genes (Figure). DCM and hypertrophic remodeling was compared using RNAseq of a mouse model of HCM; similar patterns of fibrosis with myocyte metabolic dysregulation were evident despite unique differential gene expression patterns between models. DCM caused by PLN R9C/+ is associated with early non-myocyte proliferation and later myocyte metabolic derangement possibly governed by altered PPAR signaling, and is common to DCM and HCM.

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