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15 pages, 2681 KiB

Open AccessArticle

Effects of Simvastatin on Lipid Metabolism in Wild-Type Mice and Mice with Muscle PGC-1α Overexpression

by Miljenko V. Panajatovic, Francois Singh, Stephan Krähenbühl and Jamal Bouitbir

Int. J. Mol. Sci. 2021, 22(9), 4950; https://doi.org/10.3390/ijms22094950 - 7 May 2021

Cited by 4 | Viewed by 3138

Abstract

Previous studies suggest that statins may disturb skeletal muscle lipid metabolism potentially causing lipotoxicity with insulin resistance. We investigated this possibility in wild-type mice (WT) and mice with skeletal muscle PGC-1α overexpression (PGC-1α OE mice). In WT mice, simvastatin had only minor effects [...] Read more.

Previous studies suggest that statins may disturb skeletal muscle lipid metabolism potentially causing lipotoxicity with insulin resistance. We investigated this possibility in wild-type mice (WT) and mice with skeletal muscle PGC-1α overexpression (PGC-1α OE mice). In WT mice, simvastatin had only minor effects on skeletal muscle lipid metabolism but reduced glucose uptake, indicating impaired insulin sensitivity. Muscle PGC-1α overexpression caused lipid droplet accumulation in skeletal muscle with increased expression of the fatty acid transporter CD36, fatty acid binding protein 4, perilipin 5 and CPT1b but without significant impairment of muscle glucose uptake. Simvastatin further increased the lipid droplet accumulation in PGC-1α OE mice and stimulated muscle glucose uptake. In conclusion, the impaired muscle glucose uptake in WT mice treated with simvastatin cannot be explained by lipotoxicity. PGC-1α OE mice are protected from lipotoxicity of fatty acids and triglycerides by increased the expression of FABP4, formation of lipid droplets and increased expression of CPT1b. Full article

(This article belongs to the Special Issue PGC-1s and the Control of Mitochondrial and Cellular Metabolism in Health and Disease)

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33 pages, 5734 KiB

Open AccessArticle

Pyrroloquinoline Quinone Modifies Lipid Profile, but Not Insulin Sensitivity, of Palmitic Acid-Treated L6 Myotubes

by Elżbieta Supruniuk, Agnieszka Mikłosz and Adrian Chabowski

Int. J. Mol. Sci. 2020, 21(21), 8382; https://doi.org/10.3390/ijms21218382 - 8 Nov 2020

Cited by 5 | Viewed by 3755

Abstract

Pyrroloquinoline quinone (PQQ) is a novel stimulator of mitochondrial biogenesis and cellular energy metabolism. This is the first study investigating regulatory mechanisms and metabolic responses underlying PQQ’s action in palmitate-exposed L6 myotubes. Particularly, we assessed alterations in lipid content and composition, expression of [...] Read more.

Pyrroloquinoline quinone (PQQ) is a novel stimulator of mitochondrial biogenesis and cellular energy metabolism. This is the first study investigating regulatory mechanisms and metabolic responses underlying PQQ’s action in palmitate-exposed L6 myotubes. Particularly, we assessed alterations in lipid content and composition, expression of metabolic enzymes, and changes in glucose transport. The experiments were conducted using muscle cells subjected to short (2 h) and prolonged (24 h) incubation with PQQ in a sequence of pre- and post-palmitic acid (PA) exposure. We demonstrated the opposite effects of 2 and 24 h treatments with PQQ on lipid content, i.e., a decline in the level of free fatty acids and triacylglycerols in response to short-time PQQ incubation as compared to increases in diacylglycerol and triacylglycerol levels observed after 24 h. We did not demonstrate a significant impact of PQQ on fatty acid transport. The analysis of metabolic enzyme expression showed that the vast majority of PQQ-dependent alterations cumulated in the PA/PQQ 24 h group, including elevated protein amount of peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α), sirtuin-1 (SIRT1), phosphorylated 5′AMP-activated protein kinase (pAMPK), carnitine palmitoyltransferase I (CPT1), citrate synthase (CS), fatty acid synthase (FAS), and serine palmitoyltransferase, long chain base subunit 1 (SPT1). In conclusion, the results mentioned above indicate PQQ-dependent activation of both fatty acid oxidation and lipid synthesis in order to adapt cells to palmitic acid-rich medium, although PQQ did not attenuate insulin resistance in muscle cells. Full article

(This article belongs to the Special Issue PGC-1s and the Control of Mitochondrial and Cellular Metabolism in Health and Disease)

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31 pages, 11419 KiB

Open AccessReview

PGC1s and Beyond: Disentangling the Complex Regulation of Mitochondrial and Cellular Metabolism

by Lara Coppi, Simona Ligorio, Nico Mitro, Donatella Caruso, Emma De Fabiani and Maurizio Crestani

Int. J. Mol. Sci. 2021, 22(13), 6913; https://doi.org/10.3390/ijms22136913 - 27 Jun 2021

Cited by 21 | Viewed by 4380

Abstract

Metabolism is the central engine of living organisms as it provides energy and building blocks for many essential components of each cell, which are required for specific functions in different tissues. Mitochondria are the main site for energy production in living organisms and [...] Read more.

Metabolism is the central engine of living organisms as it provides energy and building blocks for many essential components of each cell, which are required for specific functions in different tissues. Mitochondria are the main site for energy production in living organisms and they also provide intermediate metabolites required for the synthesis of other biologically relevant molecules. Such cellular processes are finely tuned at different levels, including allosteric regulation, posttranslational modifications, and transcription of genes encoding key proteins in metabolic pathways. Peroxisome proliferator activated receptor γ coactivator 1 (PGC1) proteins are transcriptional coactivators involved in the regulation of many cellular processes, mostly ascribable to metabolic pathways. Here, we will discuss some aspects of the cellular processes regulated by PGC1s, bringing up some examples of their role in mitochondrial and cellular metabolism, and how metabolic regulation in mitochondria by members of the PGC1 family affects the immune system. We will analyze how PGC1 proteins are regulated at the transcriptional and posttranslational level and will also examine other regulators of mitochondrial metabolism and the related cellular functions, considering approaches to identify novel mitochondrial regulators and their role in physiology and disease. Finally, we will analyze possible therapeutical perspectives currently under assessment that are applicable to different disease states. Full article

(This article belongs to the Special Issue PGC-1s and the Control of Mitochondrial and Cellular Metabolism in Health and Disease)

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14 pages, 908 KiB

Open AccessReview

Contribution of PGC-1α to Obesity- and Caloric Restriction-Related Physiological Changes in White Adipose Tissue

by Masaki Kobayashi, Yusuke Deguchi, Yuka Nozaki and Yoshikazu Higami

Int. J. Mol. Sci. 2021, 22(11), 6025; https://doi.org/10.3390/ijms22116025 - 2 Jun 2021

Cited by 29 | Viewed by 4968

Abstract

Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) regulates mitochondrial DNA replication and mitochondrial gene expression by interacting with several transcription factors. White adipose tissue (WAT) mainly comprises adipocytes that store triglycerides as an energy resource and secrete adipokines. The characteristics of WAT vary [...] Read more.

Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) regulates mitochondrial DNA replication and mitochondrial gene expression by interacting with several transcription factors. White adipose tissue (WAT) mainly comprises adipocytes that store triglycerides as an energy resource and secrete adipokines. The characteristics of WAT vary in response to systemic and chronic metabolic alterations, including obesity or caloric restriction. Despite a small amount of mitochondria in white adipocytes, accumulated evidence suggests that mitochondria are strongly related to adipocyte-specific functions, such as adipogenesis and lipogenesis, as well as oxidative metabolism for energy supply. Therefore, PGC-1α is expected to play an important role in WAT. In this review, we provide an overview of the involvement of mitochondria and PGC-1α with obesity- and caloric restriction-related physiological changes in adipocytes and WAT. Full article

(This article belongs to the Special Issue PGC-1s and the Control of Mitochondrial and Cellular Metabolism in Health and Disease)

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11 pages, 507 KiB

Open AccessReview

The Role of PGC1α in Alzheimer’s Disease and Therapeutic Interventions

by Bibiana C. Mota and Magdalena Sastre

Int. J. Mol. Sci. 2021, 22(11), 5769; https://doi.org/10.3390/ijms22115769 - 28 May 2021

Cited by 14 | Viewed by 3822

Abstract

The peroxisome proliferator-activated receptor co-activator-1α (PGC1α) belongs to a family of transcriptional regulators, which act as co-activators for a number of transcription factors, including PPARs, NRFs, oestrogen receptors, etc. PGC1α has been implicated in the control of mitochondrial biogenesis, the regulation of the [...] Read more.

The peroxisome proliferator-activated receptor co-activator-1α (PGC1α) belongs to a family of transcriptional regulators, which act as co-activators for a number of transcription factors, including PPARs, NRFs, oestrogen receptors, etc. PGC1α has been implicated in the control of mitochondrial biogenesis, the regulation of the synthesis of ROS and inflammatory cytokines, as well as genes controlling metabolic processes. The levels of PGC1α have been shown to be altered in neurodegenerative disorders. In the brains of Alzheimer’s disease (AD) patients and animal models of amyloidosis, PGC1α expression was reduced compared with healthy individuals. Recently, it was shown that overexpression of PGC1α resulted in reduced amyloid-β (Aβ) generation, particularly by regulating the expression of BACE1, the rate-limiting enzyme involved in the production of Aβ. These results provide evidence pointing toward PGC1α activation as a new therapeutic avenue for AD, which has been supported by the promising observations of treatments with drugs that enhance the expression of PGC1α and gene therapy studies in animal models of AD. This review summarizes the different ways and mechanisms whereby PGC1α can be neuroprotective in AD and the pre-clinical treatments that have been explored so far. Full article

(This article belongs to the Special Issue PGC-1s and the Control of Mitochondrial and Cellular Metabolism in Health and Disease)

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9 pages, 871 KiB

Open AccessReview

The Novel Role of PGC1α in Bone Metabolism

by Cinzia Buccoliero, Manuela Dicarlo, Patrizia Pignataro, Francesco Gaccione, Silvia Colucci, Graziana Colaianni and Maria Grano

Int. J. Mol. Sci. 2021, 22(9), 4670; https://doi.org/10.3390/ijms22094670 - 28 Apr 2021

Cited by 17 | Viewed by 3166

Abstract

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that [...] Read more.

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes. Full article

(This article belongs to the Special Issue PGC-1s and the Control of Mitochondrial and Cellular Metabolism in Health and Disease)

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15 pages, 6708 KiB

Open AccessReview

Role of PGC-1α in the Mitochondrial NAD⁺ Pool in Metabolic Diseases

by Jin-Ho Koh and Jong-Yeon Kim

Int. J. Mol. Sci. 2021, 22(9), 4558; https://doi.org/10.3390/ijms22094558 - 27 Apr 2021

Cited by 20 | Viewed by 5678

Abstract

Mitochondria play vital roles, including ATP generation, regulation of cellular metabolism, and cell survival. Mitochondria contain the majority of cellular nicotinamide adenine dinucleotide (NAD⁺), which an essential cofactor that regulates metabolic function. A decrease in both mitochondria biogenesis and NAD⁺ [...] Read more.

Mitochondria play vital roles, including ATP generation, regulation of cellular metabolism, and cell survival. Mitochondria contain the majority of cellular nicotinamide adenine dinucleotide (NAD⁺), which an essential cofactor that regulates metabolic function. A decrease in both mitochondria biogenesis and NAD⁺ is a characteristic of metabolic diseases, and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) orchestrates mitochondrial biogenesis and is involved in mitochondrial NAD⁺ pool. Here we discuss how PGC-1α is involved in the NAD⁺ synthesis pathway and metabolism, as well as the strategy for increasing the NAD⁺ pool in the metabolic disease state. Full article

(This article belongs to the Special Issue PGC-1s and the Control of Mitochondrial and Cellular Metabolism in Health and Disease)

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20 pages, 1130 KiB

Open AccessReview

PGC-1s in the Spotlight with Parkinson’s Disease

by Elena Piccinin, Anna Maria Sardanelli, Peter Seibel, Antonio Moschetta, Tiziana Cocco and Gaetano Villani

Int. J. Mol. Sci. 2021, 22(7), 3487; https://doi.org/10.3390/ijms22073487 - 28 Mar 2021

Cited by 49 | Viewed by 6339

Abstract

Parkinson’s disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the substantia nigra pars compacta. In recent years, the detailed analyses of both genetic and idiopathic forms of the disease [...] Read more.

Parkinson’s disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the substantia nigra pars compacta. In recent years, the detailed analyses of both genetic and idiopathic forms of the disease have led to a better understanding of the molecular and cellular pathways involved in PD, pointing to the centrality of mitochondrial dysfunctions in the pathogenic process. Failure of mitochondrial quality control is now considered a hallmark of the disease. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family acts as a master regulator of mitochondrial biogenesis. Therefore, keeping PGC-1 level in a proper range is fundamental to guarantee functional neurons. Here we review the major findings that tightly bond PD and PGC-1s, raising important points that might lead to future investigations. Full article

(This article belongs to the Special Issue PGC-1s and the Control of Mitochondrial and Cellular Metabolism in Health and Disease)

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