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
20	RESULTS — PPARα absence in cyp2a5−/− mice blunts HFD-induced obesity but enhances HFD-induced fatty liver	Using Bio-Plex mouse diabetes panel kit we screened 8 diabetes-related cytokines and found that…
21	RESULTS — PPARα absence in cyp2a5−/− mice blunts HFD-induced obesity but enhances HFD-induced fatty liver	While HFD-induced obesity was suppressed in P-A- mice, HFD-induced fatty liver was more pronounced…
22	RESULTS — PPARα absence in cyp2a5−/− mice blunts HFD-induced obesity but enhances HFD-induced fatty liver	FGF21 is regulated by PPARα (ref. 25). Serum FGF21 was higher in P+A- mice than in P-A- and P-A+…
23	DISCUSSION	Kirby et al first reported that hepatic CYP2A may regulate lipid metabolism (ref.29). Recently it…
24	DISCUSSION	It is well known that PPARα can regulate liver fatty acid oxidation and prevent fatty liver. Fasted…
25	DISCUSSION	PPARα regulates gluconeogenesis and glucose homeostasis independent of CYP2A. More severe glucose…
26	DISCUSSION	Recently it was found that failure to increase PPARα-regulated free fatty acid oxidation may be…
27	DISCUSSION	Compared with P+A- mice, P-/A- mice exhibited higher serum free fatty acids, suggesting a stronger…
28	DISCUSSION	FGF21 is a modulator of lipid metabolism and glucose homeostasis (ref.36). FGF21 attenuates…
29	DISCUSSION	FGF21 was much lower in P-/A- mice and P-/A+ mice than in P+/A- mice (Fig.4D). Free fatty acids are…
30	DISCUSSION	FGF21. In fact, leptin is a potential regulator of FGF21 (ref.43) and FGF21 can promote metabolic…
31	DISCUSSION	In this study, we evaluated glucose homeostasis during HFD feeding in a few colonies of mice. The…
32	DISCUSSION	equivalent to ppara−/−mice and our observation with glucose homeostasis in P-A+ mice is…
33	DISCUSSION	In summary, genetic association study suggests that CYP2A6 gene is associated with obesity in human…

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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