diet, metabolic disease and cancers in mouse models joe nadeau chair, department of genetics case...
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![Page 1: Diet, metabolic disease and cancers in mouse models Joe Nadeau Chair, Department of Genetics Case Western Reserve University joseph.nadeau@case.edu](https://reader030.vdocument.in/reader030/viewer/2022032803/56649e2e5503460f94b1e583/html5/thumbnails/1.jpg)
Diet, metabolic disease and cancers
in mouse models
Joe NadeauChair, Department of Genetics
Case Western Reserve [email protected]
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=+ and
Cancer risk and metabolic disease
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Diet-induced obesity:Gene - diet interactions
B6 on HFHS A/J on HFHS B6 on LFLS A/J on LFLS
0 25 50 75 100 125 1500
10
20
30
40
50
60
Age (days)
Bo
dy
We
igh
t (g
ram
s)
N ~ 25, Error Bars = 1 SD
Normaldiet
HF: 58% kcal coconut oil
LF: 11% kcal coconut oil
Calorically balanced
B6 - obese only with a HFHS diet
A/J - lean regardless of diet
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0
10
20
30
40
50
60
70
0 100 200 300 400 500
Age (days)
Mea
n W
eig
ht
(gra
ms)
B6 (35-H) (135-H)A/J (35-H) (135-H)B6 (35-L) (135-L)A/J (35-L) (135-L)
Long-term effects of high fat diet
HCC 20 of 34
No NASHNo HCC
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B6-HF (5X)
Non-alcoholic steatohepatitis (NASH) in B6
but not A/J mice-steatosis
(40% of liver mass is lipid)
after 100 days on high fat,
but not low fat diet
- hepatitis (inflammation)
- fibrosis- limited cirrhosis
after 400 days
A/J-HF (5X)(A/J LF)(B6 LF)
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Diet-induced malignant transformation and hepatocellular carcinoma (HCC)
Dysplastic nodule
HCC
Dysplastic nodulesCycles of cell damage, death and regeneration eventually lead to transformation,NASH - the ‘fertile soil’ in which transformation occurs
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Hepatocellular carcinoma (HCC)
• 3rd most common cause of cancer death worldwide• Rapidly growing cause of cancer death in U.S.• Risk factors:
1. Hepatitis B or C2. Chronic alcohol use
• Remaining 30% of “unexplained” cases are frequently associated with obesity, diabetes, non-alcoholic steatohepatitis
~70% of cases(Ken Tanabe, MGH
personal communication)
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HCCs in humans and mice
1. Biochemistry2. Histology3. mRNA profiles
1. Molecular pathways (Myc and NFkB)2. miRNA profiles (X-linked cluster)3. Predicted mRNA targets of miRNAs
Liver necrosis, cell deathLiver steatosisLiver proliferationHepatocellular carcinoma
Cardiac degeneration, cell death
Similar features in humans and mice
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HCC
No NASHNo HCCNo death
Sudden death
35 days
135 days
Diet-switch prevents HCC
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Metabolic Syndrome, NASH, HCC
On High Fat, High Sucrose Diet:
B6 A/J
Obesity
Hypertension
Insulin Resistance
Cardiovascular Disease Risk
X
X
X
X
Genetics of disease
Genetics of health
J. Nadeau and E. Topol, Nat. Genet. 2006; Shao et al. PNAS; JHN et al, in prep
X
Hepatocellularcarcinoma X
Non-alcoholicsteatohepatitis
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HCC summary
Diet-induced, rather than genetically-engineered or carcinogen-induced
Similar pathology and molecular features
Two pathways in one strain on the same diet
Diet switch reverses outcome
A similar diet modification may have important implications for prevention
of HCCs in humans
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HCC questions
Genetic control of susceptibilitychromosome substitution strains
(Singer et al. Science 2004, Shao et al. PNAS 2008 )
Mechanisms of transformationengineered mutant genes and alternative fats
Diet switch effectsphysiological mechanisms
Interventionsdrugs and diets
Biomarkers
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David BuchnerAnnie Hill
Eric Lander, Nate Berger, John Lambris, Mark Daly, Colleen Croniger, Aris Economides,
Ken Tanabe, and Shankar Subramaniam
Jon Giesinger
Soha YazbekHaifeng Shao
Stephanie Doerner