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      Lipoic Acid Prevents the Changes of Intracellular Lipid Partitioning by Free Fatty Acid

      research-article
      Author(s): * , * , , † , ‡ , § , * , * , * , * , * , *
      Publication date (Electronic):
      Journal: Gut and Liver
      Publisher: The Korean Society of Gastroenterology; the Korean Society of Gastrointestinal Endoscopy; the Korean Association for the Study of the Liver; the Korean Society of Neurogastroenterology and Motility; Korean Association for the Study of Intestinal Diseases; Korean College of Helicobacter and Upper Gastrointestinal Research; Korean Pancreatobiliary Association; Korean Society of Gastrointestinal Cancer
      Keywords: Thioctic acid, Lipotoxicity, Lipid partitioning, Non-alcoholic steatohepatitis, Liver cirrhosis

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          Abstract

          Background/Aims

          It is suggested that the hepatic lipid composition is more important than lipid quantity in the pathogenesis of non-alcoholic steatohepatitis. We examined whether lipoic acid (LA) could alter intrahepatic lipid composition and free cholesterol distribution.

          Methods

          HepG2 cells were cultured with palmitic acid (PA) with and without LA. Apoptosis, changes of the mitochondrial structure, intracellular lipid partitioning, and reactive oxygen species (ROS) activity were measured.

          Results

          Free fatty acid (FA) increased apoptosis, and LA co-treatment prevented this lipotoxicity (apoptosis in controls vs PA vs PA+LA, 0.5% vs 19.5% vs 1.6%, p<0.05). LA also restored the intracellular mitochondrial DNA copy number (553±33.8 copies vs 291±14.55 copies vs 421±21.05 copies, p<0.05) and reversed the morphological changes induced by PA. In addition, ROS was increased in response to PA and was decreased in response to LA co-treatment (41,382 relative fluorescence unit [RFU] vs 43,646 RFU vs 41,935 RFU, p<0.05). LA co-treatment increased the monounsaturated and polyunsaturated FA concentrations and decreased the total saturated FA fraction. It also prevented the movement of intracellular free cholesterol from the cell membrane to the cytoplasm.

          Conclusions

          LA opposes free FA-generated lipotoxicity by altering the intracellular lipid composition and free cholesterol distribution.

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          Most cited references34

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          Insulin resistance: a metabolic pathway to chronic liver disease.

          Elisabetta Bugianesi, Arthur McCullough, Giulio Marchesini (2005)
          Insulin resistance (IR) is the pathophysiological hallmark of nonalcoholic fatty liver disease (NAFLD), one of the most common causes of chronic liver disease in Western countries. We review the definition of IR, the methods for the quantitative assessment of insulin action, the pathophysiology of IR, and the role of IR in the pathogenesis of chronic liver disease. Increased free fatty acid flux from adipose tissue to nonadipose organs, a result of abnormal fat metabolism, leads to hepatic triglyceride accumulation and contributes to impaired glucose metabolism and insulin sensitivity in muscle and in the liver. Several factors secreted or expressed in the adipocyte contribute to the onset of a proinflammatory state, which may be limited to the liver or more extensively expressed throughout the body. IR is the common characteristic of the metabolic syndrome and its related features. It is a systemic disease affecting the nervous system, muscles, pancreas, kidney, heart, and immune system, in addition to the liver. A complex interaction between genes and the environment favors or enhances IR and the phenotypic expression of NAFLD in individual patients. Advanced fibrotic liver disease is associated with multiple features of the metabolic syndrome, and the risk of progressive liver disease should not be underestimated in individuals with metabolic disorders. Finally, the ability of insulin-sensitizing, pharmacological agents to treat NAFLD by reducing IR in the liver (metformin) and in the periphery (thiazolidinediones) are discussed.
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            Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis.

            Montserrat Marí, Francisco Caballero, Anna Colell … (2006)
            The etiology of progression from steatosis to steatohepatitis (SH) remains unknown. Using nutritional and genetic models of hepatic steatosis, we show that free cholesterol (FC) loading, but not free fatty acids or triglycerides, sensitizes to TNF- and Fas-induced SH. FC distribution in endoplasmic reticulum (ER) and plasma membrane did not cause ER stress or alter TNF signaling. Rather, mitochondrial FC loading accounted for the hepatocellular sensitivity to TNF due to mitochondrial glutathione (mGSH) depletion. Selective mGSH depletion in primary hepatocytes recapitulated the susceptibility to TNF and Fas seen in FC-loaded hepatocytes; its repletion rescued FC-loaded livers from TNF-mediated SH. Moreover, hepatocytes from mice lacking NPC1, a late endosomal cholesterol trafficking protein, or from obese ob/ob mice, exhibited mitochondrial FC accumulation, mGSH depletion, and susceptibility to TNF. Thus, we propose a critical role for mitochondrial FC loading in precipitating SH, by sensitizing hepatocytes to TNF and Fas through mGSH depletion.
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              alpha-Lipoic acid as a biological antioxidant.

              Douglas Packer, Abigail Witt, H Tritschler (1995)
              alpha-Lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, dihydrolipoate may exert prooxidant actions through reduction of iron. alpha-Lipoic acid administration has been shown to be beneficial in a number of oxidative stress models such as ischemia-reperfusion injury, diabetes (both alpha-lipoic acid and dihydrolipoic acid exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We review the properties of lipoate in terms of (1) reactions with reactive oxygen species; (2) interactions with other antioxidants; (3) beneficial effects in oxidative stress models or clinical conditions.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Gut Liver
                Journal ID (iso-abbrev): Gut Liver
                Journal ID (publisher-id): GNL
                Title: Gut and Liver
                Publisher: The Korean Society of Gastroenterology; the Korean Society of Gastrointestinal Endoscopy; the Korean Association for the Study of the Liver; the Korean Society of Neurogastroenterology and Motility; Korean Association for the Study of Intestinal Diseases; Korean College of Helicobacter and Upper Gastrointestinal Research; Korean Pancreatobiliary Association; Korean Society of Gastrointestinal Cancer
                ISSN (Print): 1976-2283
                ISSN (Electronic): 2005-1212
                Publication date (Print): March 2013
                Publication date (Electronic): 14 March 2013
                Volume: 7
                Issue: 2
                Pages: 221-227
                Affiliations
                [* ]Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.
                [† ]Department of Occupational and Environmental Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea.
                [‡ ]Department of Radiology, Hanyang University College of Medicine, Seoul, Korea.
                [§ ]Department of Pathology, Eulji University School of Medicine, Seoul, Korea.
                Author notes
                Correspondence to: Dae Won Jun. Department of Internal Medicine, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Korea. Tel: +82-2-2290-8338, Fax: +82-2-972-0068, noshin1004@ 123456google.co.kr
                Article
                DOI: 10.5009/gnl.2013.7.2.221
                PMC ID: 3607777
                PubMed ID: 23560159
                SO-VID: ee1a0c43-7ab6-42be-aab8-590481c5ab2c
                Copyright © Copyright © 2013 by the Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association for the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 21 May 2012
                Date revision received : 25 July 2012
                Date accepted : 28 July 2012
                Categories
                Subject: Original Article
                Subject: Liver, Pancreas and Biliary Tract

                ScienceOpen disciplines: Gastroenterology & Hepatology
                Keywords: thioctic acid,lipotoxicity,lipid partitioning,non-alcoholic steatohepatitis,liver cirrhosis
                Data availability:
                ScienceOpen disciplines: Gastroenterology & Hepatology
                Keywords: thioctic acid, lipotoxicity, lipid partitioning, non-alcoholic steatohepatitis, liver cirrhosis

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