CYP2A6 is associated with obesity: studies in human samples and a high fat diet mouse model.

paper Primary Public

Authors: Wang, Kesheng; Chen, Xue; Ward, Stephen C; Liu, Ying; Ouedraogo, Youssoufou; Xu, Chun; Cederbaum, Arthur I; Lu, Yongke
Year: 2019
Journal: International journal of obesity (2005)
PMID: 29568101
DOI: 10.1038/s41366-018-0037-x
PMCID: PMC6102101

Figure 1

HFD-induced obesity is more severe in cyp2a5−/− mice than in cyp2a5+/+ mice. (A) Body weight. *P<0.05, compared with WT HFD group. (B) Serum triglyceride. *P<0.05, compared with CD group; #P<0.05, compared with WT HFD group. (C) Serum glucose. *P<0.05, compared with CD group; #P<0.05, compared with WT HFD group. (D) Glucose tolerance test. * P<0.05, compared with WT HFD group. (E) Insulin tolerance test. * P<0.05, compared with WT HFD group. CD, control diet; HFD, high fat diet; KO, cyp2a5−/− mice; WT, cyp2a5+/+ mice.

Figure 2

HFD-induced nonalcoholic fatty liver is more severe in cyp2a5−/− mice than in cyp2a5+/+ mice. (A) Liver triglyceride. *P<0.05, compared with CD group; #P<0.05, compared with WT HFD group. (B) Liver section H&E staining. (C) Pathological quantification: steatosis score. *P<0.05, compared with CD group; #P<0.05, compared with WT HFD group. (D) Liver expression of CYP2E1, CYP2A5, ADRP, PPARα and FGF21. (E) Activities of microsomal CYP2E1 and CYP2A5. *P<0.05, compared with CD group. (F) Serum FGF21 level. *P<0.05, compared with WT CD group.

Figure 3

HFD does not induce obesity in P-A- mice. (A) Body weight. (B). Adipose tissue H&E staining shows size of adipocytes. (C) Glucose tolerance test. (D) Pyruvate tolerance test. * P<0.05, compared to P+A- CD group. (E) Serum leptin. (F) Serum grhelin.

Figure 4

HFD-induced fatty liver is more severe in P-A- mice than in P+A- mice. (A) Liver section H&E staining. Arrows show lipid droplets. (B) Serum levels of free fatty acids. (C) Serum β-hydroxylbutyrate. (D) Serum FGF21. (E) Serum adiponectin. (F) Serum CTRP3. *P<0.05, compared with P-A- CD group; $ P<0.05, compared with P-A+ CD group; # P<0.05, compared to P-A- HFD Group; & P<0.05, compared with P-A+ HFD group.

#	Section	Preview
0	INTRODUCTION	Dysfunction in lipid metabolism and glucose homeostasis leads to obesity, which is related to…
1	INTRODUCTION	CYP2A is a subfamily of CYPs, which includes but does not limit to CYP2A6 in human and CYP2A5 in…
2	INTRODUCTION	In the liver sections from patients with alcoholic liver diseases, CYP2A expression was detected to…
3	INTRODUCTION	Peroxisome proliferator-activated receptor α (PPARα) is a major to regulator for hepatic lipid…
4	MATERIALS AND METHODS — HUMAN SUBJECTS — The SAGE (Study of Addiction: Genetics and Environment) sample	The SAGE is a comprehensive genome-wide association study (GWAS) using approximately 4,000 unrelated…
5	MATERIALS AND METHODS — HUMAN SUBJECTS — The SAGE (Study of Addiction: Genetics and Environment) sample	class. The mean and ranges of age are similar in each weight class. Obesity was determined by body…
6	MATERIALS AND METHODS — HUMAN SUBJECTS — Statistical analyses	Hardy-Weinberg equilibrium was tested for all of the SNPs in individuals with normal weight as…
7	MATERIALS AND METHODS — ANIMAL EXPERIMENTATION — Animals and Treatments	The colony of cyp2a5−/− mice was created by crossing male C57BL/6 cyp2a5−/− mice (ref. 22)…
8	MATERIALS AND METHODS — ANIMAL EXPERIMENTATION — Animals and Treatments	The female, 6–8 weeks mice (5 mice/group by randomization) were used to induce obesity and…
9	MATERIALS AND METHODS — ANIMAL EXPERIMENTATION — Glucose tolerance test, insulin tolerance test, and pyruvate tolerance test	For Glucose tolerance test and pyruvate tolerance test, the mice were subjected to an overnight fast…
10	MATERIALS AND METHODS — ANIMAL EXPERIMENTATION — Liver Histology	Liver sections with hematoxylin and eosin (H&E) staining were used for pathological evaluation as…
11	MATERIALS AND METHODS — ANIMAL EXPERIMENTATION — Liver microsomal CYP2E1 and CYP2A5 Activity	For liver microsomes preparation and microsomal CYP2E1 and CYP2A5 (coumarin 7-hydroxylase) activity…
12	MATERIALS AND METHODS — ANIMAL EXPERIMENTATION — Western Blotting	The SDS-PAGE and chemiluminescence imaging was carried out as described before (ref. 9–12).…
13	RESULTS — Genetic association study: CYP2A6 gene is associated with obesity	Single marker analysis showed that 3 SNPs (rs8192729, rs7256108, and rs7255443) in the CYP2A6 gene…
14	RESULTS — After HFD feeding, cyp2a5−/− mice exhibit more body weight gain than cyp2a5+/+ mice	The female cyp2a5−/− and cyp2a5+/+ mice were fed HFD or CD for 3 months. After HFD feeding, the…
15	RESULTS — After HFD feeding, cyp2a5−/− mice exhibit more body weight gain than cyp2a5+/+ mice	mice did (Fig 1 D). However, after 30min of insulin injection, there was no significant difference…
16	RESULTS — HFD-induced fatty liver is more pronounced in cyp2a5−/− mice than in cyp2a5+/+ mice	After HFD feeding, liver contents of triglyceride were increased in cyp2a5−/− mice to a greater…
17	RESULTS — HFD-induced fatty liver is more pronounced in cyp2a5−/− mice than in cyp2a5+/+ mice	hepatic microsomes isolated from cyp2a5−/− mice (Fig 2 E). Even though hepatic activity coumarin…
18	RESULTS — PPARα absence in cyp2a5−/− mice blunts HFD-induced obesity but enhances HFD-induced fatty liver	Female PPARα and CYP2A5 double knockout mice (P-A- mice), their female littermates not expressing…
19	RESULTS — PPARα absence in cyp2a5−/− mice blunts HFD-induced obesity but enhances HFD-induced fatty liver	panel) and P-A+ mice (Fig. 3C right panel); HFD feeding worsen the glucose intolerance in P+A- mice…

Name	Type
ACTB	gene
adipocyte size	phenotype
adiponectin	drug
ADIPOQ	gene
ADRP local	gene
African American	cohort
alcohol	phenotype
alcohol dependence	phenotype
alcoholic liver disease	phenotype
Alcoholic liver disease patients local	cohort
aspartate transaminase local	drug
Blood glucose reduction local	phenotype
BMI	phenotype
body mass index	phenotype
body weight	phenotype
C1QTNF3 local	gene
Caucasian	cohort
Class II and III obesity local	phenotype
class III obesity local	phenotype
class II obesity local	phenotype
class I obesity local	phenotype
Class I obesity local	phenotype
collagen fiber local	phenotype
control diet local	drug
Control diet local	cohort
Control diet local	drug
controls	cohort
controls with normal weight local	cohort
coumarin	drug
coumarin 7-hydroxylase activity local	phenotype
Coumarin 7-hydroxylase activity local	phenotype
CTRP3 local	drug
CYP1B1	gene
Cyp2a5	gene
CYP2A5+/+ local	variant
CYP2A5−/− local	variant
cyp2a5−/− colony local	cohort
cyp2a5 knockout mice local	cohort
cyp2a5+/+ mice local	cohort
cyp2a5−/− mice local	cohort
CYP2A5+/+ mice local	cohort
CYP2A5−/− mice local	cohort
Cyp2a5+/+ mouse local	cohort
Cyp2a5−/− mouse local	cohort
CYP2A6	gene
CYP2A6 SNPs local	variant
CYP2A7	gene
CYP2A7 SNPs local	variant
CYP2E1	gene
Cyp4a	gene
diabetes	phenotype
diet-induced obesity	phenotype
drug dependence	phenotype
dyslipidemia	phenotype
East Tennessee State University local	cohort
elevated serum FGF21 local	phenotype
European ancestry	cohort
FAS local	gene
fatty acids	drug
fatty liver	phenotype
Female 6–8 weeks mice local	cohort
Female Cyp2a5 knockout mice local	cohort
Female Cyp2a5 wild-type mice local	cohort
Fgf21	gene
FGFR1	gene
GENEVA initiative local	cohort
ghrelin	drug
GIP	drug
GLP-1 local	drug
glucagon	drug
gluconeogenesis	phenotype
glucose	drug
Glucose challenge local	drug
glucose homeostasis	phenotype
Glucose homeostasis dysfunction local	phenotype
glucose intolerance	phenotype
glucose tolerance test local	drug
Glucose tolerance test	phenotype
glycerol	drug
hematoxylin and eosin local	drug
hepatic CYP2A expression absent local	phenotype
hepatic steatosis	phenotype
HFD	drug
high-fat diet	drug
High-fat diet local	cohort
High-fat diet (HFD) local	cohort
human subjects	cohort
hyperglycemia	phenotype
Hypertriglyceridemia local	phenotype
impaired metabolism capacity local	phenotype
increased ADRP expression local	phenotype
increased liver triglyceride local	phenotype
insulin	drug
insulin resistance	phenotype
Insulin tolerance test local	phenotype
ketogenesis	phenotype
LEP	gene
leptin	drug
less obesity local	phenotype
lipid droplets	phenotype
lipid metabolism	phenotype
Lipid metabolism dysfunction local	phenotype
liver gluconeogenesis local	phenotype
liver microsomes local	drug
methionine and choline deficient diet local	drug
mice	cohort
Monosodium glutamate local	drug
Monosodium glutamate-induced obese mice local	cohort
non-alcoholic fatty liver local	phenotype
nonalcoholic fatty liver local	phenotype
Non-alcoholic fatty liver local	phenotype
Non-alcoholic fatty liver disease	phenotype
Non-alcoholic fatty liver disease patients local	cohort
normal weight	phenotype
obesity	phenotype
obesity I local	phenotype
obesity II+III local	phenotype
ob/ob local	phenotype
ob/ob mice	cohort
overweight	phenotype
PAI-1 local	drug
P+/A+ mice local	cohort
P+/A- mice local	cohort
P+A- mice local	cohort
P-/A+ mice local	cohort
P-/A- mice local	cohort
P-A+ mice local	cohort
P-A- mice local	cohort
PLIN2 local	gene
potassium chloride	drug
PPARA	gene
PPARA−/− local	variant
ppara−/− mice local	cohort
PPARA−/− mice local	cohort
PPARα	gene
PPARα−/− mice	cohort
Purina standard chow local	drug
pyruvate	drug
pyruvate intolerance local	phenotype
pyruvate tolerance test local	drug
Pyruvate tolerance test local	phenotype
Resistin local	drug
rs7251418 local	variant
rs7255443 local	variant
rs7256108 local	variant
rs8192729 local	variant
SAGE	cohort
SAGE dataset	cohort
severe fatty liver local	phenotype
sinusoids local	phenotype
SNP	cohort
triglycerides	phenotype
water	drug
wild-type mice	cohort
WT control local	cohort
β-hydroxy butyrate local	drug
β-hydroxybutyrate local	drug

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