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      Metabolic Spectrum of Liver Failure in Type 2 Diabetes and Obesity: From NAFLD to NASH to HCC

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          Abstract

          Liver disease is the spectrum of liver damage ranging from simple steatosis called as nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC). Clinically, NAFLD and type 2 diabetes coexist. Type 2 diabetes contributes to biological processes driving the severity of NAFLD, the primary cause for development of chronic liver diseases. In the last 20 years, the rate of non-viral NAFLD/NASH-derived HCC has been increasing rapidly. As there are currently no suitable drugs for treatment of NAFLD and NASH, a class of thiazolidinediones (TZDs) drugs for the treatment of type 2 diabetes is sometimes used to improve liver failure despite the risk of side effects. Therefore, diagnosis, prevention, and treatment of the development and progression of NAFLD and NASH are important issues. In this review, we will discuss the pathogenesis of NAFLD/NASH and NAFLD/NASH-derived HCC and the current promising pharmacological therapies of NAFLD/NASH. Further, we will provide insights into “adipose-derived adipokines” and “liver-derived hepatokines” as diagnostic and therapeutic targets from NAFLD to HCC.

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          Most cited references350

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          The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases.

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            Global cancer statistics.

            The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.
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              Metabolic endotoxemia initiates obesity and insulin resistance.

              Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                26 April 2021
                May 2021
                : 22
                : 9
                : 4495
                Affiliations
                [1 ]Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; khm7607@ 123456kribb.re.kr (H.K.); dasom89@ 123456kribb.re.kr (D.S.L.); anth0291@ 123456kribb.re.kr (T.H.A.); h18509@ 123456kribb.re.kr (H.-J.P.); wkkim@ 123456kribb.re.kr (W.K.K.)
                [2 ]Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
                Author notes
                [* ]Correspondence: khbae@ 123456kribb.re.kr (K.-H.B.); kjoh80@ 123456kribb.re.kr (K.-J.O.); Tel.: +82-42-860-4268 (K.-H.B.); +82-42-879-8265 (K.-J.O.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-5596-4320
                https://orcid.org/0000-0001-8339-767X
                https://orcid.org/0000-0002-5868-2556
                https://orcid.org/0000-0002-2224-7202
                Article
                ijms-22-04495
                10.3390/ijms22094495
                8123490
                33925827
                e6cee863-8225-4a52-b370-f200b588e25c
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 02 April 2021
                : 23 April 2021
                Categories
                Review

                Molecular biology
                non-alcholic fatty liver disease (nafld),non-alcoholic steatohepatitis (nash),hepatocellular carcinoma (hcc),type 2 diabetes,obesity,adipokines,hepatokines

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