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      Quantitative Assessment of Liver Steatosis and Affected Pathways with Molecular Imaging and Proteomic Profiling

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      1 , 2 , 2 , , 1 ,
      Scientific Reports
      Nature Publishing Group UK

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          Abstract

          Current assessment of non-alcoholic fatty liver disease (NAFLD) with histology is time-consuming, insensitive to early-stage detection, qualitative, and lacks information on etiology. This study explored alternative methods for fast and quantitative assessment of NAFLD with hyperspectral stimulated Raman scattering (SRS) microscopy and nanofluidic proteomics. Hyperspectral SRS microscopy quantitatively measured liver composition of protein, DNA, and lipid without labeling and sensitively detected early-stage steatosis in a few minutes. On the other hand, nanofluidic proteomics quantitatively measured perturbations to the post-translational modification (PTM) profiles of selective liver proteins to identify affected cellular signaling and metabolic pathways in a few hours. Perturbations to the PTM profiles of Akt, 4EBP1, BID, HMGCS2, FABP1, and FABP5 indicated abnormalities in multiple cellular processes including cell cycle regulation, PI3K/Akt/mTOR signaling cascade, autophagy, ketogenesis, and fatty acid transport. The integrative deployment of hyperspectral SRS microscopy and nanofluidic proteomics provided fast, sensitive, and quantitative assessment of liver steatosis and affected pathways that overcame the limitations of histology.

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          Most cited references36

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          Autophagy in the liver: functions in health and disease

          Autophagy is a conserved process critically involved in many cellular functions. In this Review, Ueno and Komatsu discuss the role and regulation of autophagy in healthy liver and in hepatic disease states, including NAFLD, α1-antitrypsin deficiency and viral hepatitis.
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            Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus.

            Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers, and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance. Phosphorylation of Akt at S473 (ref. 5) and T308 (ref. 6) activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle progression, another cancer hallmark. Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of the cyclin A2 allele in the mouse olfactory bulb leads to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, cyclin A2-deletion-induced cellular apoptosis in mouse embryonic stem cells is partly rescued by S477D/T479E-Akt1, supporting a physiological role for cyclin A2 in governing Akt activation. Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.
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              Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.

              Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis). Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                jxcheng@bu.edu
                tle5@roseman.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                26 February 2018
                26 February 2018
                2018
                : 8
                : 3606
                Affiliations
                [1 ]ISNI 0000 0004 0383 2160, GRID grid.417517.1, Department of Biomedical Sciences, , College of Medicine, Roseman University of Health Sciences, 10530 Discovery Drive, ; Las Vegas, NV 89135 USA
                [2 ]ISNI 0000 0004 1936 7558, GRID grid.189504.1, Departments of Electrical and Computer Engineering & Biomedical Engineering, , College of Engineering, Boston University, 8 St. Mary’s St, ; Boston, MA 02215 USA
                Article
                22082
                10.1038/s41598-018-22082-6
                5826939
                29483581
                8e93bcb7-6096-4be2-89ee-f7b1ed2f7403
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 November 2017
                : 16 February 2018
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