Browsing by Subject "High fat diet"

Now showing 1 - 3 of 3
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    FOXO transcription factors protect against the diet-induced fatty liver disease
    (SpringerNature, 2017-03-16) Pan, Xiaoyan; Zhang, Yang; Kim, Hyeong-Geug; Liangpunsakul, Suthat; Dong, X. Charlie; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Forkhead O transcription factors (FOXOs) have been implicated in glucose and lipid homeostasis; however, the role of FOXOs in the development of nonalcoholic fatty liver disease (NAFLD) is not well understood. In this study, we designed experiments to examine the effects of two different diets-very high fat diet (HFD) and moderately high fat plus cholesterol diet (HFC)-on wildtype (WT) and liver-specific Foxo1/3/4 triple knockout mice (LTKO). Both diets induced severe hepatic steatosis in the LTKO mice as compared to WT controls. However, the HFC diet led to more severe liver injury and fibrosis compared to the HFD diet. At the molecular levels, hepatic Foxo1/3/4 deficiency triggered a significant increase in the expression of inflammatory and fibrotic genes including Emr1, Ccl2, Col1a1, Tgfb, Pdgfrb, and Timp1. Thus, our data suggest that FOXO transcription factors play a salutary role in the protection against the diet-induced fatty liver disease.
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    Indole Alleviates Diet-induced Hepatic Steatosis and Inflammation in a Manner Involving Myeloid Cell PFKFB3
    (Wolters Kluwer, 2020-10) Ma, Linqiang; Li, Honggui; Hu, Jinbo; Zheng, Juan; Zhou, Jing; Botchlett, Rachel; Matthews, Destiny; Zeng, Tianshu; Chen, Lulu; Xiao, Xiaoqiu; Athrey, Giri; Threadgill, David W.; Li, Qingsheng; Glaser, Shannon; Francis, Heather; Meng, Fanyin; Li, Qifu; Alpini, Gianfranco; Wu, Chaodong; Medicine, School of Medicine
    Background and aims: Indole is a microbiota metabolite that exerts anti-inflammatory responses. However, the relevance of indole to human non-alcoholic fatty liver disease (NAFLD) is not clear. It also remains largely unknown whether and how indole acts to protect against NAFLD. The present study sought to examine the association between the circulating levels of indole and liver fat content in human subjects and explore the mechanisms underlying indole actions in mice with diet-induced NAFLD. Approach and results: In a cohort of 137 subjects, the circulating levels of indole were reversely correlated with body mass index. In addition, the circulating levels of indole in obese subjects were significantly lower than those in lean subjects and were accompanied with increased liver fat content. At the whole-animal level, treatment of high-fat diet (HFD)-fed C57BL/6J mice with indole caused significant decreases in the severity of hepatic steatosis and inflammation. In cultured cells, indole treatment stimulated the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a master regulatory gene of glycolysis, and suppressed macrophage proinflammatory activation in a PFKFB3-dependent manner. Moreover, myeloid cell-specific PFKFB3 disruption exacerbated the severity of HFD-induced hepatic steatosis and inflammation and blunted the effect of indole on alleviating diet-induced NAFLD phenotype. Conclusions: Taken together, our results demonstrate that indole is relevant to human NAFLD and capable of alleviating diet-induced NAFLD phenotypes in mice in a myeloid cell PFKFB3-dependent manner. Therefore, indole mimetic and/or macrophage-specific PFKFB3 activation may be the viable preventive and/or therapeutic approaches for inflammation-associated diseases including NAFLD.
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    Role of DHS in translation control of islet β-cell replication during high fat induced obesity and glucose intolerance
    (2017-11) Levasseur, Esther Marie; Mirmira, Raghu
    Insulin resistance in liver, muscle, and adipose tissue almost invariably occurs during obesity. To compensate, the insulin-producing β-cell increases insulin production by expanding cellular mass. The inability of the β-cell to fully compensate leads to hyperglycemia and ultimately type 2 diabetes. The enzyme deoxyhypusine synthase (DHS) catalyzes the spermidine-dependent posttranslational modification of Lys50 of eukaryotic translation initiation factor 5A (eIF5A) to form hypusine (Hyp). Studies have demonstrated this modification of eIF5A to contribute to cellular proliferation in cancerous cells, but its role in the physiologic proliferation of islet β-cells is unknown. I hypothesized eIF5A-Hyp to be required for the proliferation of islet β cells during the early phase of insulin resistance, allowing the β-cell to respond to the increased demand for insulin to maintain glucose homeostasis. To test this hypothesis, deletion of DHS was induced post-developmentally in β-cells by crossing Dhs-fl/fl mice with MIP1-CreERT mice, and animals were fed for 1 or 4 weeks with a 60% kcal from fat diet (HFD) or normal chow diet (NCD, 16% kcal from fat diet). NCD-fed and HFD-fed animals had normal glucose homeostasis after one week feeding, regardless of genotype. However, after 4 weeks of HFD, KO mice had significantly worse glucose intolerance compared to control mice. eIF5A-Hyp levels increased in β-cells of control animals and as expected remained low in the KO mice. β-cell proliferation was significantly increased after 1 week of HFD as measured by PCNA staining, however KO mice showed no increase. Cyclin D2 protein, but not mRNA, was increased in control animals fed a HFD; this protein increase was not observed in KO animals. Furthermore, polyribosomal profile of isolated islets of 1 week HFD-fed mice showed the Ccnd2 mRNA bound to the monoribosome fractions in the KO animals compared to the controls, resulting in changes of global translation. Interestingly, Ccnd1 polyribosome to monoribosome ratio showed no changes in translation compared to Ccnd2. Taken together, these results suggest that DHS (and, consequently, eIF5A-Hyp) is necessary for the adaptive proliferative and functional response of β-cells during high fat diet induced obesity and glucose intolerance.