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Sex-specific hepatic lipid and bile acid metabolism alterations in Fancd2-deficient mice following dietary challenge.

ABSTRACT: Defects in the Fanconi anemia (FA) DNA damage-response pathway result in genomic instability, developmental defects, hematopoietic failure, cancer predisposition, and metabolic disorders. The endogenous sources of damage contributing to FA phenotypes and the links between FA and metabolic disease remain poorly understood. Here, using mice lacking the Fancd2 gene, encoding a central FA pathway component, we investigated whether the FA pathway protects against metabolic challenges. Fancd2 -/- and wildtype (WT) mice were fed a standard diet (SD), a diet enriched in fat, cholesterol, and cholic acid (Paigen diet), or a diet enriched in lipid alone (high-fat diet (HFD)). Fancd2 -/- mice developed hepatobiliary disease and exhibited decreased survival when fed a Paigen diet but not a HFD. Male Paigen diet-fed mice lacking Fancd2 had significant biliary hyperplasia, increased serum bile acid concentration, and increased hepatic pathology. In contrast, female mice were similarly impacted by Paigen diet feeding regardless of Fancd2 status. Upon Paigen diet challenge, male Fancd2 -/- mice had altered expression of genes encoding hepatic bile acid transporters and cholesterol and fatty acid metabolism proteins, including Scp2/x, Abcg5/8, Abca1, Ldlr, Srebf1, and Scd-1 Untargeted lipidomic profiling in liver tissue revealed 132 lipid species, including sphingolipids, glycerophospholipids, and glycerolipids, that differed significantly in abundance depending on Fancd2 status in male mice. We conclude that the FA pathway has sex-specific impacts on hepatic lipid and bile acid metabolism, findings that expand the known functions of the FA pathway and may provide mechanistic insight into the metabolic disease predisposition in individuals with FA.

SUBMITTER: Moore ES

PROVIDER: S-EPMC6816084 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Sex-specific hepatic lipid and bile acid metabolism alterations in Fancd2-deficient mice following dietary challenge.

Moore Elizabeth S ES Daugherity Erin K EK Karambizi David I DI Cummings Bethany P BP Behling-Kelly Erica E Schaefer Deanna M W DMW Southard Teresa L TL McFadden Joseph W JW Weiss Robert S RS

The Journal of biological chemistry 20190821 43

Defects in the Fanconi anemia (FA) DNA damage-response pathway result in genomic instability, developmental defects, hematopoietic failure, cancer predisposition, and metabolic disorders. The endogenous sources of damage contributing to FA phenotypes and the links between FA and metabolic disease remain poorly understood. Here, using mice lacking the Fancd2 gene, encoding a central FA pathway component, we investigated whether the FA pathway protects against metabolic challenges. Fancd ...[more]

PMID: 31434739

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Project description:BackgroundInadequate copper intake and increased fructose consumption represent two important nutritional problems in the USA. Dietary copper-fructose interactions alter gut microbial activity and contribute to the development of nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine whether dietary copper-fructose interactions alter gut microbial activity in a sex-differential manner and whether sex differences in gut microbial activity are associated with sex differences in hepatic steatosis.MethodsMale and female weanling Sprague-Dawley (SD) rats were fed ad libitum with an AIN-93G purified rodent diet with defined copper content for 8 weeks. The copper content is 6 mg/kg and 1.5 mg/kg in adequate copper diet (CuA) and marginal copper diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (F) (w/v) as the only drink during the experiment. Body weight, calorie intake, plasma alanine aminotransferase, aspartate aminotransferase, and liver histology as well as liver triglyceride were evaluated. Fecal microbial contents were analyzed by 16S ribosomal RNA (16S rRNA) sequencing. Fecal and cecal short-chain fatty acids (SCFAs) were determined by gas chromatography-mass spectrometry (GC-MS).ResultsMale and female rats exhibit similar trends of changes in the body weight gain and calorie intake in response to dietary copper and fructose, with a generally higher level in male rats. Several female rats in the CuAF group developed mild steatosis, while no obvious steatosis was observed in male rats fed with CuAF or CuMF diets. Fecal 16S rRNA sequencing analysis revealed distinct alterations of the gut microbiome in male and female rats. Linear discriminant analysis (LDA) effect size (LEfSe) identified sex-specific abundant taxa in different groups. Further, total SCFAs, as well as, butyrate were decreased in a more pronounced manner in female CuMF rats than in male rats. Of note, the decreased SCFAs are concomitant with the reduced SCFA producers, but not correlated to hepatic steatosis.ConclusionsOur data demonstrated sex differences in the alterations of gut microbial abundance, activities, and hepatic steatosis in response to dietary copper-fructose interaction in rats. The correlation between sex differences in metabolic phenotypes and alterations of gut microbial activities remains elusive.

Project description:Background: There is heterogeneity in neurosensory alterations following mild traumatic brain injury. Commonly assessed neurosensory symptoms following head injury include symptom reports and measures of oculomotor impairment, auditory changes, and vestibular impairment. Hypothesis/Purpose: Neurosensory alterations are prevalent acutely following mild traumatic brain injury secondary to blunt head trauma during collegiate varsity sports and may vary by sex and sport. Study Design: Retrospective study of a large collegiate athletic database. Methods: Analyses were performed using an established single University dataset of 177 male and female collegiate varsity athletes who were diagnosed with concussion/mild traumatic brain injury between September 2013 and October 2019. Descriptive and comparative analyses were performed on individual and grouped acute concussion assessments pertaining to neurosensory alterations obtained within 72 h of injury using components of the Sports Concussion Assessment Tool Version 5 and Vestibular/Ocular-Motor Screening. Results: Females had significantly more abnormal smooth pursuit (p-value: 0.045), convergence (p-value: 0.031), and visual motion sensitivity tests results (p-value: 0.023) than males. There were no differences in neurosensory alterations when grouped by overall auditory, vestibular, or oculomotor impairments. The majority of sports-related concussions occurred during football (50, 28.25%), wrestling (21, 11.86%), water polo (15, 8.47%), and basketball (14, 7.91%). Abnormal vestibular assessments were high in these top four sports categories, but statistically significant differences in overall auditory, vestibular, or oculomotor impairments were not reached by individual sport. However, water polo players had higher abnormal individual assessments related to balance reports on the sideline (60.00%, p-value: 0.045) and in the clinic setting (57.14%, p-value: 0.038) as compared to all other sports. Conclusion: While neurosensory alterations are prevalent in both male and female athletes acutely post-concussion, females have a higher incidence of abnormalities in smooth pursuit, convergence, and visual motion sensitivity and may benefit from early rehabilitation.

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Sex-specific hepatic lipid and bile acid metabolism alterations in Fancd2-deficient mice following dietary challenge.

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Sex-specific hepatic lipid and bile acid metabolism alterations in <i>Fancd2-</i>deficient mice following dietary challenge.

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