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      Neonatal overfeeding in mice aggravates the development of methionine and choline-deficient diet-induced steatohepatitis in adulthood


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          Overfeeding in early life is associated with obesity and insulin resistance in adulthood. In the present study, a well-characterized mouse model was used to investigate whether neonatal overfeeding increases susceptibility to the development of non-alcoholic steatohepatitis (NASH) following feeding with a methionine and choline- deficient (MCD) diet. Neonatal overfeeding was induced by adjusting litters to 3 pups per dam (small litter size, SL) in contrast to 10 pups per dam as control (normal litter size, NL). At 11 weeks of age, mice were fed with standard (S) or a methionine and choline-deficient (MCD) diet for 4 weeks. Glucose tolerance tests, tissue staining with haematoxylin and eosin, oil-red O and immunohistochemistry for F4/80, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed. Compared with NL mice, SL mice exhibited higher body weight gain from 2 weeks of age throughout adulthood, and more profound glucose intolerance as adults. Sterol regulatory element-binding protein 1c and fatty acid synthase mRNA expression levels in liver were upregulated in SL mice at 3 weeks of age. MCD diet induced typical NASH, especially in SL-MCD mice, evidenced by marked fat accumulation, macrovescular steatosis, ballooned hepatocytes, inflammatory cells infiltration and tumour necrosis factor-α mRNA upregulation in the liver, as well as increased alanine aminotransferase and aspartate aminotransferase levels in the serum. There were no significant differences in liver fibrosis in all groups. Overfeeding during early life exhibited effect with administration of MCD diet in inducing adverse effects on the metabolic function and in promoting the progression of NASH in mice, possibly mediated through dysregulated lipid metabolism in hepatocytes and aggravated hepatic inflammation.

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          Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

          Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.
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            Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production.

            The mechanisms triggering nonalcoholic steatohepatitis (NASH) remain poorly defined. Kupffer cells are the first responding cells to hepatocyte injuries, leading to TNFα production, chemokine induction, and monocyte recruitment. The silencing of TNFα in myeloid cells reduces NASH progression. Increase of TNFα-producing Kupffer cells is crucial for triggering NASH via monocyte recruitment. Myeloid cells-targeted silencing of TNFα might be a tenable therapeutic approach. Nonalcoholic steatohepatitis (NASH), characterized by lipid deposits within hepatocytes (steatosis), is associated with hepatic injury and inflammation and leads to the development of fibrosis, cirrhosis, and hepatocarcinoma. However, the pathogenic mechanism of NASH is not well understood. To determine the role of distinct innate myeloid subsets in the development of NASH, we examined the contribution of liver resident macrophages (i.e. Kupffer cells) and blood-derived monocytes in triggering liver inflammation and hepatic damage. Employing a murine model of NASH, we discovered a previously unappreciated role for TNFα and Kupffer cells in the initiation and progression of NASH. Sequential depletion of Kupffer cells reduced the incidence of liver injury, steatosis, and proinflammatory monocyte infiltration. Furthermore, our data show a differential contribution of Kupffer cells and blood monocytes during the development of NASH; Kupffer cells increased their production of TNFα, followed by infiltration of CD11b(int)Ly6C(hi) monocytes, 2 and 10 days, respectively, after starting the methionine/choline-deficient (MCD) diet. Importantly, targeted knockdown of TNFα expression in myeloid cells decreased the incidence of NASH development by decreasing steatosis, liver damage, monocyte infiltration, and the production of inflammatory chemokines. Our findings suggest that the increase of TNFα-producing Kupffer cells in the liver is crucial for the early phase of NASH development by promoting blood monocyte infiltration through the production of IP-10 and MCP-1.
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              Animal models of NASH: getting both pathology and metabolic context right.

              Non-alcoholic fatty liver disease (NAFLD) is the most common cause of referral to liver clinics, and its progressive form, non-alcoholic steatohepatitis (NASH), can lead to cirrhosis and end-stage liver disease. The main risk factors for NAFLD/NASH are the metabolic abnormalities commonly observed in metabolic syndrome: insulin resistance, visceral obesity, dyslipidemia and altered adipokine profile. At present, the causes of progression from NAFLD to NASH remain poorly defined, and research in this area has been limited by the availability of suitable animal models of this disease. In the past, the main models used to investigate the pathogenesis of steatohepatitis have either failed to reproduce the full spectrum of liver pathology that characterizes human NASH, or the liver pathology has developed in a metabolic context that is not representative of the human condition. In the last few years, a number of models have been described in which the full spectrum of liver pathology develops in an appropriate metabolic context. In general, the underlying cause of metabolic defects in these models is chronic caloric overconsumption, also known as overnutrition. Overnutrition has been achieved in a number of different ways, including forced feeding, administration of high-fat diets, the use of genetically hyperphagic animals, or a combination of these approaches. The purpose of the present review is to critique the liver pathology and metabolic abnormalities present in currently available animal models of NASH, with particular focus on models described in approximately the last 5 years.

                Author and article information

                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                05 January 2018
                March 2019
                05 January 2018
                : 6
                : 1
                : 68-77
                [a ]Laboratory of Lipid & Glucose Metabolism, PR China
                [b ]Department of Clinical Nutrition, The First Affiliated Hospital of Chongqing Medical University, PR China
                [c ]School of Public Health and Management, Chongqing Medical University, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing, 400016, PR China
                Author notes
                []Corresponding author. Laboratory of Lipid & Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, 1Youyi Road, Chongqing, 400016, PR China. bshaw2001@ 123456163.com

                These authors contribute equally to this study.

                © 2018 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 28 November 2017
                : 23 December 2017

                inflammation,insulin resistance,neonatal overfeeding,non-alcoholic steatohepatitis,obesity


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