Linking Hepatic Transcriptional Changes to High–Fat Diet Induced Physiology for Diabetes-Prone and Obese-Resistant Mice

Alevizos, Ilias; Misra, Jatin; Bullen, John W.; Basso, Giuseppe; Kelleher, Joanne K.; Mantzoros, Christos S.; Stephanopoulos, Gregory

doi:10.4161/cc.6.13.4380

Cited by 11 publications

(8 citation statements)

References 20 publications

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“…C57BL/6J and A/J mice have been commonly used for models of obesity, diabetes, fatty liver, and the metabolic syndrome (Alevizos et al 2007;Hall et al 2010;Nishina et al 1993). Several studies have determined that C57BL/6J are sensitive to and that A/J mice are resistant to metabolic syndrome phenotypes, and our findings are similar to published data.…”

Section: Discussionsupporting

confidence: 82%

Identification of eQTLs for hepatic Xbp1 s and Socs3 gene expression in mice fed a high-fat, high caloric diet

Pasricha¹,

Anderson²,

Hall

et al. 2015

Z Gastroenterol

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Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent form of human hepatic disease and feeding mice a high-fat, high-caloric (HFHC) diet is a standard model of NAFLD. To better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. Two-hundred sixty-five (A/J · C57BL/6J) F 2 male mice were fed a HFHC diet for 8 wk. eQTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1s and Socs3. We identified two overlapping loci for Xbp1s and Socs3 on Chr 1 (164.0-185.4 Mb and 174.4-190.5 Mb, respectively) and Chr 11 (41.1-73.1 Mb and 44.0-68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9-117.4 Mb). C57BL/6J-Chr 11 A/J / NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1s and Socs3 gene expression (P , 0.05), whereas C57BL/6J-Chr 1 A/J / NaJ mice retained the C57BL/6J phenotype. In addition, we replicated the eQTLs on Chr 1 and Chr 12 (LOD scores $3.5) using mice from the BXD murine reference panel challenged with CCl 4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and Chr 11, and consomic mice confirmed that replacing the C57BL/6J Chr 11 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases.

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Section: Discussionsupporting

confidence: 82%

Identification of eQTLs for hepatic Xbp1 s and Socs3 gene expression in mice fed a high-fat, high caloric diet

Pasricha¹,

Anderson²,

Hall

et al. 2015

Z Gastroenterol

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“…This rapid increase in insulin in Klf11 −/− mice did not persist either at 60 or 120 min. As in many other studies that tried to model diabetes-associated alterations in mice, including Hnf1a , Gck , and Glut2 (37–40), Klf11 −/− animals did not ultimately develop diabetes, likely because of concomitant alterations of metabolic pathways in peripheral tissues (41, 42). This notion is supported by our gene expression profiling of these mice, which demonstrates that Klf11 −/− mice display abnormal expression of several metabolic enzymes in adipose and muscle tissue (supplemental Fig.…”

Section: Resultsmentioning

confidence: 69%

Disruption of a Novel Krüppel-like Transcription Factor p300-regulated Pathway for Insulin Biosynthesis Revealed by Studies of the c.-331 INS Mutation Found in Neonatal Diabetes Mellitus

Bonnefond

Lomberk

Buttar

et al. 2011

Journal of Biological Chemistry

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Krüppel-like transcription factors (KLFs) have elicited significant attention because of their regulation of essential biochemical pathways and, more recently, because of their fundamental role in the mechanisms of human diseases. Neonatal diabetes mellitus is a monogenic disorder with primary alterations in insulin secretion. We here describe a key biochemical mechanism that underlies neonatal diabetes mellitus insulin biosynthesis impairment, namely a homozygous mutation within the insulin gene (INS) promoter, c.-331C>G, which affects a novel KLF-binding site. The combination of careful expression profiling, electromobility shift assays, reporter experiments, and chromatin immunoprecipitation demonstrates that, among 16 different KLF proteins tested, KLF11 is the most reliable activator of this site. Congruently, the c.-331C>G INS mutation fails to bind KLF11, thus inhibiting activation by this transcription factor. Klf11−/− mice recapitulate the disruption in insulin production and blood levels observed in patients. Thus, these data demonstrate an important role for KLF11 in the regulation of INS transcription via the novel c.-331 KLF site. Lastly, our screening data raised the possibility that other members of the KLF family may also regulate this promoter under distinct, yet unidentified, cellular contexts. Collectively, this study underscores a key role for KLF proteins in biochemical mechanisms of human diseases, in particular, early infancy onset diabetes mellitus.

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“…In this sense, the C57BL/6J-fed mice exhibited signs of insulin resistance, while the A/J mice did not after a long-term consumption of a high fat diet [87]. These findings were considered related to differential gene expressions [88], and therefore these experiments pursued.…”

Section: Effect Of Dietary Fat Contentmentioning

confidence: 99%

The Use of Transcriptomics to Unveil the Role of Nutrients in Mammalian Liver

Osada

2013

ISRN Nutrition

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Liver is the organ primarily responding to diet, and it is crucial in determining plasma carbohydrate, protein, and lipid levels. In addition, it is mainly responsible for transformation of xenobiotics. For these reasons, it has been a target of transcriptomic analyses. In this review, we have covered the works dealing with the response of mammalian liver to different nutritional stimuli such as fasting/feeding, caloric restriction, dietary carbohydrate, cholesterol, fat, protein, bile acid, salt, vitamin, and oligoelement contents. Quality of fats or proteins has been equally addressed, and has the influence of minor dietary components. Other compounds, not purely nutritional as those represented by alcohol and food additives, have been included due to their relevance in processed food. The influence has been studied not only on mRNA but also on miRNA. The wide scope of the technology clearly reflects that any simple intervention has profound changes in many metabolic parameters and that there is a synergy in response when more compounds are included in the intervention. Standardized arrays to systematically test the same genes in all studies and analyzing data to establish patterns of response are required, particularly for RNA sequencing. Moreover, RNA is a valuable, easy-screening ally but always requires further confirmation.

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Linking Hepatic Transcriptional Changes to High–Fat Diet Induced Physiology for Diabetes-Prone and Obese-Resistant Mice

Cited by 11 publications

References 20 publications

Identification of eQTLs for hepatic Xbp1 s and Socs3 gene expression in mice fed a high-fat, high caloric diet

Identification of eQTLs for hepatic Xbp1 s and Socs3 gene expression in mice fed a high-fat, high caloric diet

Disruption of a Novel Krüppel-like Transcription Factor p300-regulated Pathway for Insulin Biosynthesis Revealed by Studies of the c.-331 INS Mutation Found in Neonatal Diabetes Mellitus

The Use of Transcriptomics to Unveil the Role of Nutrients in Mammalian Liver

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