Cyp2b-null male mice are susceptible to diet-induced obesity and perturbations in lipid homeostasis

Heintz, Melissa M.; Kumar, Ramiya; Rutledge, Meredith M; Baldwin, William S.

doi:10.1016/j.jnutbio.2019.05.004

Cited by 22 publications

(42 citation statements)

References 86 publications

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“…In our recently published research, C57Bl/6J (B6)-Cyp2b9/10/13-null (Cyp2b-null) mice lacking the predominantly hepatic Cyp2b members, Cyp2b9, Cyp2b10, and Cyp2b13, are diet-induced obese in males with moderate increases in steatosis. Interestingly, the Cyp2b-null male mice developed some steatosis regardless of diet; however, they showed very little hepatic inflammation, which is unusual, suggesting Cyp2bnull mice may be protected from developing NASH [33]. This study was only carried out for 10 weeks and new research indicates that B6 mice fed a high fructose + 42% Kcal HFD for up to 22-weeks failed to form NASH following NAFLD development.…”

Section: Introductionmentioning

confidence: 89%

“…Animal care and associated procedures were approved by Clemson University's Institutional Animal Care and Use committee. Cyp2b9/10/13-null (Cyp2b-null) mice were developed using CRISPR/Cas9 technology on the C57Bl/6J (B6) background mice as previously described [33,35]. Wildtype (WT) B6 mice were purchased from The Jackson Laboratory (Bar Harbor, ME, USA) at 6 weeks of age and were acclimated for 4 weeks prior to treatment.…”

Section: Choline-deficient L-amino Acid-defined High-fat Diet (Cdahfd)mentioning

confidence: 99%

“…bleed. During week 6, glucose tolerance was determined following an intraperitoneal injection of 1g/kg of their body weight of D-glucose (Sigma Ultra, St. Louis, MO USA) with blood glucose readings every 20 min for the first hour and every 30 min for the second hour as described previously [33,38].…”

Section: Plos Onementioning

confidence: 99%

“…Significantly (p < 0.05) enriched GO terms were visualized in Revigo, which reduces enriched term redundancy and displays the remaining GO terms in a scatterplot [43]. Differentially expressed genes acoss treatment groups were annotated using PANTHER (http://www.pantherdb.org/) and InterPro [44], and differentially expressed genes between CDAHFD-fed Cyp2b-null and CDAHFD-fed WT mice were entered into KEGG Mapper [45] to determine and visualize biochemical pathways perturbed by diet-induced NASH and/or a lack of Cyp2b enzymes [33].…”

Section: Rna Sequencing (Rnaseq)mentioning

confidence: 99%

“…We used our previously developed Cyp2b-null mouse model [33,35] to test whether a lack of Cyp2b plays a role in the progression of liver disease. Cyp2b-null and WT mice (n = 9) were fed either a choline-deficient, L-amino acid-defined, high fat diet (CDAHFD) or normal diet (ND) for 8 weeks.…”

Section: Introductionmentioning

confidence: 99%

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Gender differences in diet-induced steatotic disease in Cyp2b-null mice

et al. 2020

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Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease; however, progression to nonalcoholic steatohepatitis (NASH) is associated with most adverse outcomes. CYP2B metabolizes multiple xeno-and endobiotics, and male Cyp2b-null mice are dietinduced obese (DIO) with increased NAFLD. However, the DIO study was not performed long enough to assess progression to NASH. Therefore, to assess the role of Cyp2b in fatty liver disease progression from NAFLD to NASH, we treated wildtype (WT) and Cyp2b-null mice with a normal diet (ND) or choline-deficient, L-amino acid-defined high fat diet (CDAHFD) for 8 weeks and determined metabolic and molecular changes. CDAHFD-fed WT female mice gained more weight and had greater liver and white adipose tissue mass than their Cyp2b-null counterparts; males experienced diet-induced weight loss regardless of genotype. Serum biomarkers of liver injury increased in both CDAHFD-fed female and male mice; however CDAHFD-fed Cyp2b-null females exhibited significantly lower serum ALT, AST, and ASP concentrations compared to WT mice, indicating Cyp2b-null females were protected from liver injury. In both genders, hierarchical clustering of RNA-seq data demonstrates several gene ontologies responded differently in CDAHFD-fed Cyp2b-null mice compared to WT mice (lipid metabolism > fibrosis > inflammation). Oil Red O staining and direct triglycerides measurements confirmed that CDAHFD-fed Cyp2b-null females were protected from NAFLD. CDAHFD-fed Cyp2b-null mice showed equivocal changes in fibrosis with transcriptomic and serum markers suggesting less inflammation due to glucocorticoid-mediated repression of immune responses. In contrast to females, CDAHFD-fed Cyp2b-null males had higher triglyceride levels. Results indicate that female Cyp2b-null mice are protected from NAFLD while male Cyp2b-null mice are more susceptible to NAFLD, with few significant changes in NASH development. This study confirms that increased NAFLD development does not necessarily lead to progressive NASH. Furthermore, it indicates a role for Cyp2b in fatty liver disease that differs based on gender.

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Section: Introductionmentioning

confidence: 89%

Section: Choline-deficient L-amino Acid-defined High-fat Diet (Cdahfd)mentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Section: Rna Sequencing (Rnaseq)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gender differences in diet-induced steatotic disease in Cyp2b-null mice

et al. 2020

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Maternal obesogenic diet during pregnancy and its impact on fetal hepatic function in baboons

Meakin,

Nathanielsz,

et al. 2024

Obesity

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ObjectiveMaternal obesity (MO) increases the risk of later‐life liver disease in offspring, especially in males. This may be due to impaired cytochrome P450 (CYP) enzyme activity driven by an altered maternal‐fetal hormonal milieu. MO increases fetal cortisol concentrations that may increase CYP activity; however, glucocorticoid receptor (GR)‐mediated signaling can be modulated by alternative GR isoform expression. We hypothesized that MO induces sex‐specific changes in GR isoform expression and localization that contribute to reduced hepatic CYP activity.MethodsNonpregnant, nulliparous female baboons were assigned to either an ad libitum control diet or a high‐fat, high‐energy diet (HF‐HED) at 9 months pre pregnancy. At 165 days' gestation (term = 180 days), fetal liver samples were collected (n = 6/sex/group). CYP activity was quantified using functional assays, and GR was measured using quantitative RT‐PCR and Western blot.ResultsCYP3A activity was reduced in the HF‐HED group, whereas CYP2B6 activity was reduced in HF‐HED males only. Total GR expression was increased in the HF‐HED group. Relative nuclear expression of the antagonistic GR isoform GRβ was increased in HF‐HED males only.ConclusionsReduced CYP activity in HF‐HED males may be driven in part by dampened hepatic‐specific glucocorticoid signaling via altered GR isoform expression. These findings highlight targetable mechanisms that may reduce later‐life sex‐specific disease risk.

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Brain‐derived neurotrophic factor knock‐out mice develop non‐alcoholic steatohepatitis

Ichimura‐Shimizu,

Kojima,

Suzuki

et al. 2023

The Journal of Pathology

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While brain‐derived neurotrophic factor (BDNF), which is a growth factor associated with cognitive improvement and the alleviation of depression symptoms, is known to regulate food intake and body weight, the role of BDNF in peripheral disease is not fully understood. Here, we show that reduced BDNF expression is associated with weight gain and the chronic liver disease non‐alcoholic steatohepatitis (NASH). At 10 months of age, BDNF‐heterozygous (BDNF+/−) mice developed symptoms of NASH: centrilobular/perivenular steatosis, lobular inflammation with infiltration of neutrophils, ballooning hepatocytes, and fibrosis of the liver. Obesity and higher serum levels of glucose and insulin – major pathologic features in human NASH – were dramatic. Dying adipocytes were surrounded by macrophages in visceral fat, suggesting that chronic inflammation occurs in peripheral organs. RNA sequencing (RNA‐seq) studies of the liver revealed that the most significantly enriched Gene Ontology term involved fatty acid metabolic processes and the modulation of neutrophil aggregation, pathologies that well characterise NASH. Gene expression analysis by RNA‐seq also support the notion that BDNF+/− mice are under oxidative stress, as indicated by alterations in the expression of the cytochrome P450 family and a reduction in glutathione S‐transferase p, an antioxidant enzyme. Histopathologic phenotypes of NASH were also observed in a knock‐in mouse (BDNF+/pro), in which the precursor BDNF is inefficiently converted into the mature form of BDNF. Lastly, as BDNF reduction causes overeating and subsequent obesity, a food restriction study was conducted in BDNF+/pro mice. Pair‐fed BDNF+/pro mice developed hepatocellular damage and showed infiltration of inflammatory cells, including neutrophils in the liver, despite having body weights and blood parameters that were comparable to those of controls. This is the first report demonstrating that reduced BDNF expression plays a role in the pathogenic mechanism of NASH, which is a hepatic manifestation of metabolic syndrome. © 2023 The Pathological Society of Great Britain and Ireland.

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Cyp2b-null male mice are susceptible to diet-induced obesity and perturbations in lipid homeostasis

Cited by 22 publications

References 86 publications

Gender differences in diet-induced steatotic disease in Cyp2b-null mice

Gender differences in diet-induced steatotic disease in Cyp2b-null mice

Maternal obesogenic diet during pregnancy and its impact on fetal hepatic function in baboons

Brain‐derived neurotrophic factor knock‐out mice develop non‐alcoholic steatohepatitis

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