Treating fatty liver disease by modulating mitochondrial pyruvate metabolism

Colca, Jerry R.; McDonald, William Graham; McCommis, Kyle S.; Finck, Brian N.

doi:10.1002/hep4.1036

Cited by 21 publications

(13 citation statements)

References 38 publications

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“…Amiodarone or valproate accumulate in mitochondria and induce inhibition of fatty acid oxidation and electron transfer chain (Berson et al, 1998). In support of the key role of mitochondria in NAFLD, recent data indicated the critical role of the mitochondrial pyruvate carrier MPC, a heterologous complex made of MPC1 and MPC2 proteins in the inner mitochondrial membrane (Colca et al, 2017). The complex is required for the entry of pyruvate that is synthetized in the cytosol, in the mitochondrial matrix, where it will be further metabolized.…”

Section: Lipids Mitochondria and Agingmentioning

confidence: 99%

Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases

Giorgi

Marchi

Simões

et al. 2018

International Review of Cell and Molecular Biology

284

162

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Aging has been linked to several degenerative processes that, through the accumulation of molecular and cellular damage, can progressively lead to cell dysfunction and organ failure. Human aging is linked with a higher risk for individuals to develop cancer, neurodegenerative, cardiovascular, and metabolic disorders. The understanding of the molecular basis of aging and associated diseases has been one major challenge of scientific research over the last decades. Mitochondria, the center of oxidative metabolism and principal site of reactive oxygen species (ROS) production, are crucial both in health and in pathogenesis of many diseases. Redox signaling is important for the modulation of cell functions and several studies indicate a dual role for ROS in cell physiology. In fact, high concentrations of ROS are pathogenic and can cause severe damage to cell and organelle membranes, DNA, and proteins. On the other hand, moderate amounts of ROS are essential for the maintenance of several biological processes, including gene expression. In this review, we provide an update regarding the key roles of ROS-mitochondria cross talk in different fundamental physiological or pathological situations accompanying aging and highlighting that mitochondrial ROS may be a decisive target in clinical practice.

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Section: Lipids Mitochondria and Agingmentioning

confidence: 99%

Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases

Giorgi

Marchi

Simões

et al. 2018

International Review of Cell and Molecular Biology

284

162

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“…While pioglitazone is traditionally thought to act as an agonist of PPARγ, others have hypothesized that the benefits of pioglitazone, but not the side effects of the drug, can be separated from PPAR activity 79, 80. These investigators postulated that TZDs attenuate mitochondrial pyruvate carrier activity and that new selective mitochondrial pyruvate carrier modulators will share the therapeutic benefits of TZDs but not the side effects that limit TZD use 79, 80. Two such agents, MSDC-0602K (Cirius Therapeutics, San Diego, CA), and PXL065 (formerly DRX-065 from DeuteRx) (Poxel, Lyon, France) are presently in development for NASH (Table 1).…”

Section: Nuclear Hormone Receptorsmentioning

confidence: 99%

Metabolic Targets in Nonalcoholic Fatty Liver Disease

Esler

Bence

2019

Cellular and Molecular Gastroenterology and Hepatology

111

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“…MSDC-0602K is a mitochondrial target of thiazolidinediones, which produces several of the benefits of PPAR-γ agonists with potentially less impact on weight gain and more impact on attenuating fibrosis. 58 It is currently in phase IIa trial. 34 , 59 IVA-337 (lanifibranor) is a pan-PPAR agonist (α/δ/γ) that has been shown to reduce steatosis, reduce inflammation, reduce ballooning, improve insulin sensitivity, and reduce fibrosis in models of NASH.…”

Section: Introductionmentioning

confidence: 99%

Obesity and nonalcoholic fatty liver disease: current perspectives

Sarwar¹,

Pierce²,

Koppe³

2018

DMSO

203

136

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Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of chronic liver disease due to an increase in the prevalence of obesity. The development of NASH leads to an increase in morbidity and mortality. While the first line of treatment is lifestyle modifications, including dietary changes and increased physical activity, there are no approved pharmacological treatment agents for NAFLD and NASH currently. Due to its complex pathophysiology, different pathways are under investigation for drug development with the focus on metabolic pathways, inflammation, and slowing or reversing fibrosis. There are several agents advancing in clinical trials, and promising results have been seen with drugs that affect hepatic steatosis, inflammation, and fibrosis. This review will provide an overview on NAFLD and some of the mechanisms of disease that are being targeted with pharmacologic agents.

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Treating fatty liver disease by modulating mitochondrial pyruvate metabolism

Cited by 21 publications

References 38 publications

Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases

Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases

Metabolic Targets in Nonalcoholic Fatty Liver Disease

Obesity and nonalcoholic fatty liver disease: current perspectives

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