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      Neurotropin Inhibits Lipid Accumulation by Maintaining Mitochondrial Function in Hepatocytes via AMPK Activation

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          Abstract

          The accumulation of lipid droplets in the cytoplasm of hepatocytes, known as hepatic steatosis, is a hallmark of non-alcoholic fatty liver disease (NAFLD). Inhibiting hepatic steatosis is suggested to be a therapeutic strategy for NAFLD. The present study investigated the actions of Neurotropin (NTP), a drug used for chronic pain in Japan and China, on lipid accumulation in hepatocytes as a possible treatment for NAFLD. NTP inhibited lipid accumulation induced by palmitate and linoleate, the two major hepatotoxic free fatty acids found in NAFLD livers. An RNA sequencing analysis revealed that NTP altered the expression of mitochondrial genes. NTP ameliorated palmitate-and linoleate-induced mitochondrial dysfunction by reversing mitochondrial membrane potential, respiration, and β-oxidation, suppressing mitochondrial oxidative stress, and enhancing mitochondrial turnover. Moreover, NTP increased the phosphorylation of AMPK, a critical factor in the regulation of mitochondrial function, and induced PGC-1β expression. Inhibition of AMPK activity and PGC-1β expression diminished the anti-steatotic effect of NTP in hepatocytes. JNK inhibition could also be associated with NTP-mediated inhibition of lipid accumulation, but we did not find the association between AMPK and JNK. These results suggest that NTP inhibits lipid accumulation by maintaining mitochondrial function in hepatocytes via AMPK activation, or by inhibiting JNK.

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          Most cited references40

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          Data quality aware analysis of differential expression in RNA-seq with NOISeq R/Bioc package

          As the use of RNA-seq has popularized, there is an increasing consciousness of the importance of experimental design, bias removal, accurate quantification and control of false positives for proper data analysis. We introduce the NOISeq R-package for quality control and analysis of count data. We show how the available diagnostic tools can be used to monitor quality issues, make pre-processing decisions and improve analysis. We demonstrate that the non-parametric NOISeqBIO efficiently controls false discoveries in experiments with biological replication and outperforms state-of-the-art methods. NOISeq is a comprehensive resource that meets current needs for robust data-aware analysis of RNA-seq differential expression.
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            Regulation of lipid stores and metabolism by lipophagy.

            K. Liu, M Czaja (2013)
            Intracellular lipids are stored in lipid droplets (LDs) and metabolized by cytoplasmic neutral hydrolases to supply lipids for cell use. Recently, an alternative pathway of lipid metabolism through the lysosomal degradative pathway of autophagy has been described and termed lipophagy. In this form of lipid metabolism, LD triglycerides (TGs) and cholesterol are taken up by autophagosomes and delivered to lysosomes for degradation by acidic hydrolases. Free fatty acids generated by lipophagy from the breakdown of TGs fuel cellular rates of mitochondrial β-oxidation. Lipophagy therefore functions to regulate intracellular lipid stores, cellular levels of free lipids such as fatty acids and energy homeostasis. The amount of lipid metabolized by lipophagy varies in response to the extracellular supply of nutrients. The ability of the cell to alter the amount of lipid targeted for autophagic degradation depending on nutritional status demonstrates that this process is selective. Intracellular lipids themselves regulate levels of autophagy by unclear mechanisms. Impaired lipophagy can lead to excessive tissue lipid accumulation such as hepatic steatosis, alter hypothalamic neuropeptide release to affect body mass, block cellular transdifferentiation and sensitize cells to death stimuli. Future studies will likely identify additional mechanisms by which lipophagy regulates cellular physiology, making this pathway a potential therapeutic target in a variety of diseases.
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              New insights into PGC-1 coactivators: redefining their role in the regulation of mitochondrial function and beyond.

              Members of the PGC-1 family of coactivators have been revealed as key players in the regulation of energy metabolism. Early gain- and loss-of-function studies led to the conclusion that all members of the PGC-1 family (PGC-1α, PGC-1β and PRC) play redundant roles in the control of mitochondrial biogenesis by regulating overlapping gene expression programs. Regardless of this, all PGC-1 coactivators also appeared to differ in the stimuli to which they respond to promote mitochondrial gene expression. Although PGC-1α was found to be induced by different physiological or pharmacological cues, PGC-1β appeared to be unresponsive to such stimuli. Consequently, it has long been widely accepted that PGC-1α acts as a mediator of mitochondrial biogenesis induced by cues that signal high-energy needs, whereas the role of PGC-1β is restricted to the maintenance of basal mitochondrial function. By contrast, the function of PRC appears to be restricted to the regulation of gene expression in proliferating cells. However, recent studies using tissue-specific mouse models that lack or overexpress different PGC-1 coactivators have provided emerging evidence not only supporting new roles for PGC-1s, but also redefining some of the paradigms related to the precise function and mode of action of PGC-1 coactivators in mitochondrial biogenesis. The present review discusses some of the new findings regarding the control of mitochondrial gene expression by PGC-1 coactivators in a tissue-specific context, as well as newly-uncovered functions of PGC-1s beyond mitochondrial biogenesis, and their link to pathologies, such as diabetes, muscular dystrophies, neurodegenerative diseases or cancer.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                06 August 2020
                2020
                : 11
                : 950
                Affiliations
                [1] 1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles , CA, United States
                [2] 2E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine , Shanghai, China
                [3] 3Department of Pharmacological Research, Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Co., Ltd. , Osaka, Japan
                [4] 4Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA, United States
                [5] 5Smidt Heart Institute, Cedars-Sinai Medical Center , Los Angeles, CA, United States
                Author notes

                Edited by: Stephen J. Pandol, Cedars-Sinai Medical Center, United States

                Reviewed by: Anna Alisi, Bambino Gesù Children’s Hospital (IRCCS), Italy; Sung Hwan Ki, Chosun University, South Korea

                *Correspondence: Ekihiro Seki, Ekihiro.Seki@ 123456cshs.org

                This article was submitted to Gastrointestinal Sciences, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2020.00950
                7424056
                32848877
                239de110-2c5c-4861-bbb2-3fc2e69ad18f
                Copyright © 2020 Wang, Wang, Xu, Tu, Hsin, Stotland, Kim, Liu, Naiki, Gottlieb and Seki.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 January 2020
                : 14 July 2020
                Page count
                Figures: 9, Tables: 0, Equations: 0, References: 67, Pages: 18, Words: 0
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                ampk,fatty liver,mitochondria,lipid metabolism,liver
                Anatomy & Physiology
                ampk, fatty liver, mitochondria, lipid metabolism, liver

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