Transcript PPT 자료 다운받기 - 대한 기독교 여자 절제회

2008. 11. 15 절제회 세미나발표
Studying
on Alcoholic Liver injury and Diabetes
국립보건연구원
생명의과학센터
김원호
KNIH
발표순서
Ⅰ. 알코올 연구 배경
Ⅱ. 알코올 연구 동향
Ⅲ. 알코올 연구
KNIH
사업배경: 국내외 환경변화
만성질환으로 인한 의료비증가
물질남용으로 인한 사회적 비용증가
10억불
160
140
148
120
100
98.6
80
66.9
60
72
40
20
0
정신질환
알코올
약물
담배
Souece: Rice & Miller, 1992
알코올성질환 진단 및 치료법 개발의
민간지원 부족
 저출산  고령화 사회진입 및 알코올 기인 만성질환 증가
 알코올 중독성질환에 대한 국가관리의 필요성 증대
KNIH
알코올성질환 연구 추진배경
 알코올 중독 장애 급증
• ’01년 조사: 알코올 남용 및 의존으로 인한 알코올 사용장애 인구가
전 인구의 6.8 %인 221만 명으로 보고
 알코올로 인한 만성질환 발생률 증가
• 심장질환, 간질환, 소화기질환, 뇌혈관질환, 암, 고혈압, 당뇨, 우울증
등의 발생률이 급격히 증가
KNIH
Necessity of Research
Alcohol-related Diseases
for
 Sudden Increase of Population with AUD
• According to 2001 survey, the population with alcohol use
disorders (alcohol abuse & alcoholism) is estimated up to 2.21
million (6.8% of total population)
Table 1. Prevalence of Alcohol Use Disorders
(Unit: Persons)
Total
Male
Female
Category
No. of
patients
Estimated
Prevalence(
%)
No. of
patients
Estimated
Prevalence(
%)
No. of
patients
Estimated
Prevalence(
%)
Total
2,212,175
6.8
1,799,625
11.0
412,550
2.6
Alcohol
Abuse
820,678
2.5
674,156
4.1
146,522
0.9
Alcohol
Dependence
1,391,497
4.3
1,125,469
6.9
266,028
1.7
* Sources: Epidemiological Study of Psychiatric Illnesses, Ministry of Health & Welfare, 2001
KNIH
국내 알코올 소비 현황
 성인 음주 현황
성인 및 여성 음주율이 지속적으로 증가
– 성인(20~59세) 음주율(’05 건강영양조사)
 성인:35.4%(’95) → 76.5%(’01) → 83.9%(’05)
 여성:14.7%(’95) → 33.9%(’01) → 77.0%(’05)
100
90
80
70
60
50
40
30
20
10
0
90
76.5
77
80
83.9
70
67.4
60
50
53.1
35.4
40
33.9
30
20
14.7
10
0
1995
1998
2001
2005
성인음주율
여성음주율
KNIH
국내 알코올 소비량 추이
탁주
소주
알코올 소비현황 추이(kl)
3,500,000
3,000,000
2,500,000
2,000,000
1,500,000
1,000,000
500,000
0
2002년
탁 주 129,217
맥 주 1,961,699
소 주 878,741
총 계 3,139,166
2003년
2004년
140,697
1,903,504
932,553
3,144,950
161,653
1,928,492
928,365
3,185,436
2005년
맥주
총계
2006년
166,319
170,165
1,838,154 1,880,049
929,840
959,534
3,093,961 3,171,402
2007년
172,342
1,982,697
963,678
3,290,770
KNIH
우리나라 15세 이상 알코올 소비량 (OECD 2007)
 8.9ℓ(’95) → 9.2ℓ(’99) → 7.9ℓ(’01)
8.6ℓ(’03) → 8.1ℓ(’05)
 OECD국가 알코올 평균소비 : 9.5ℓ(’05)
알코올소비량
9.5
9
8.5
알코올소비량
8
7.5
7
1995
1997
1999
2001
2003
2005
KNIH
현재 음주자의 하루 평균 음주량 (19세 이상)
(단위 : %)
구분
소주1-2잔
3-4잔
5-6잔
7잔이상
전체
32.5
21.7
12.6
33.3
남자
15.1
18.2
15.7
51.1
여자
53.9
25.9
8.7
11.5
 출처 : 2005년 국민건강영양조사
 2007년 기준 : 성인 1인당 소주 72병, 맥주 107병 소비
KNIH
알코올 사용장애인구 : 16 ~ 64세 인구 중
180만 명
 정신장애 일년 유병율 및 추정환자수(’06
역학조사)
(단위 : %, 천명)
남자
구분
유병
률
여자
추정환
자
유병
률
전체
추정환
자
유병
률
추정환
자
모든 정신장애
(니코틴/알코올
제외)
5.5
878
11.2
1,763
8.3
2,641
알코올사용장애
8.7
1,393
2.5
403
5.6
1,795
KNIH
Necessity of Research
Alcohol-related Diseases
for
 Increase of Alcohol-related Diseases and Costs
 Due to increase of drinking, the incidence of alcohol-related
diseases has strongly increased (2002 World Health Report)
-Liver diseases (hepatitis, cirrhosis), Gastrointestinal diseases,
Cerebrovascular & Cardiovascular Diseases, Malignancy, etc
 Socioeconomic cost of alcohol-caused diseases : about
USA $ 2.954 billion
(Unit: billion $)
Cost
Total
Cancer
Cardiovascular
Disease
2.95
0.95
0.13
Hypertensive
Disease
Gastrointestinal
Disease
Mental
Disorders
0.09
0.66
1.12
Sources: Index Development to make moderate drinking and Alcohol-related policy, Hun-Jong Song, 2005
KNIH
Necessity of Research
Alcohol-related Diseases
for
 Increase of Death by Alcohol Drinking
 Death by drinking only has turned out to be about 22,000 persons
(8.7% of total death) (Gwang-Gi Kim, 2001)
10
9
8.7% (2001)
2004, WHO
Death ratio (%)
8
7
6
4.8%
4.5%
5
5.3%
3%
4
3
2
1
0
USA
Canada
Germany
New
Zealand
South Korea
KNIH
술로 인한 연간 사회경제적 손실비용(’04년)
Direct Cost (Medical Cost)
1 billion $
GDP 약 3%인 20조 990억 원(’08.2/연세대)
Property Damage
•직접의료비: 1조724억
& Administrative
•직접비의료비 : 3,755억
Individual
•1조4,479억 7%Family
• 재산피해: 5,043억
Cost
• 주류소비지출:
4조 4,702억
(Traffic Accident
Low Quality of Life
and Fire)
Domestic Violence
4조 9,745억
3.5 billion $
Disease
Poverty
22%
Death
Indirect Cost
(Low Productivity
and Premature
Death)
11.4 billion $
Alcohol Drinking
$ 15.8 billion
12조 9,161억 Accident •(Drinking생산성 감소비: 7조 8,050억
Low Work Efficiency
related Accident
• 조기사망자 생산인력 감소:
Absence
and Fire) 5조
& Crime
4,111억 등
(Violence, etc.)
Job
직접비용
Society
간접비용
기타비용
Sources: Won-Jae Jung, Yonsei Univ., 2005
KNIH
Mission
알코올부담의 획기적 감소통한 국민건강증진 및 삶의 질 향상
예방관리
조기검진
생애전주기에 따른 알코올 및
위험인자 특성연구
치료지원
진단치료기술 개발 연구
모니터링
알코올 관련정책수립근거마련
역학조사사업
(알코올지도 작성)
홈페이지 운영
지역거점 알코올상담센터
통합운영
알코올 질환 센터
통합프로토콜 작성
KNIH
알코올중독성질환 연구 추진 계획
진단기술
유병률/관련요인
지표 개발
실태 및 추이분석
치료제개발
시료자원 확보
알코올관련 DB구축
유전적 생화학적 특성
코호트 구축
질병발생기전
실험모델개발
KNIH
연구사업 사업추진체계
국민건강증진을 통한 삶의 질 향상
외부 알코올관련기관
알코올 중독질환센터
역학조사연구
역학조사연구
프로토콜 작성
질병기전연구
유병률 조사
기초임상연구
정보제공
첨단대량 분석
자료기술협력
진단치료제개발
지역거점센터
통합운영 및
정보 DB화
국내외공동협력연구
병원
학교 및 연구소
산업체
KNIH
알코올 연구동향
KNIH
Alcohol Across the Lifespan
 NIAAA Strategic Plan for Research, 2008-2013
1. how alcohol perturbs development of the embryo and fetus: FASD 개선 방법
2. how genetic and environmental factors contribute to drinking initiation and the
development of alcohol dependence : lifespan의 적절한 단계에서 specific risk factors를
제어하는 예방전략수립
3. the factors that influence the common phenomenon of naturally “aging out” of
alcohol dependence : 새로운 치료접근법개발 및 alcoholism 치료 시 행동변화 유도 방법
4. how alcohol use produces functional and structural changes in the nervous system:
brain에서의 specific molecular targets에 직접적인 영향을 미쳐 행동 개선 및 치료에 도움되
To understand the interactions of alcohol with stages of life will
는방법
enable to address the prevention and treatment of alcohol problems
5. How the products of alcohol metabolism contribute to the development of alcohol-
in a life stage-appropriate manner
induced diseases of the liver, digestive systm, lung, heart, brain, endocrine ad
immune system: 이들 disorders를 예방 치료할 수 있는 방법
KNIH
생애전주기에 따른 알코올사용 및 알코올 문제에
대한 연구 강화
● 생애전주기에 따른 알코올 사용 및 알코올문제에 대한 연구 강화
KNIH
Effect of Alcohol on
Organ Function
KNIH
Alcohol and Chronic Diseases
Diabetes
Alcohol
Consumption
KNIH
Mortality and the Burden of Disease Attributable to Leading
Global Risk Factors by World Bank Region in 2006
Mortality (9th rank)
Burden of diseases (5th rank)
KNIH
청소년의 음주 문제
KNIH
KNIH
인물과 술
전쟁
긴장
간질
술로 긴장 완화
및 간질 순화 승리
신성병
페르시아제국정복
술
파괴와 노획, 무희
폭음 뒤 쓰러져 12일
중독
동안 고열후 죽음
간질환자 알렉산더: 긴장감이 고조되면 어느 순간 발작으로 경련. 쓰러져 거품을 무는 증세
천재들이 천부적으로 타고나는 병, 다시 말해 신이 특별히 아끼는 사람에게 내리는 '신성병
(神聖病)'
KNIH
KNIH
Effect of Alcohol on Brain
Brain
• acts as a depressant.
• decreases the activity of the nervous system.
• produces a number of behavioral problems.
• Behavioral effects of acetaldehyde
Locomoter effect – stimulant or depressant
Hypnotic effect – strong sedative effect
Reinforcing effect – self administration, drug hedonic
property…eventually leads to addiction
Anxiolytic effect
Amnesic effect – impairment of memory acquisition through
an inhibition of LTP. (Blackout)
KNIH
Effect of Alcohol on nervous System
KNIH
The Problems of Female Drinking
What is fetal alcohol syndrome?
• Characteristic facial feature
• Growth retardation
• Central nervous system neuro-developmental abnormality
KNIH
Study on Fetal Alcohol Syndrome (FAS)
Brain of baby with no
exposure to alcohol
Brain of baby with heavy
prenatal exposure to alcohol
Alcohol Exposure During Stages of Pregnancy
1.
Alcohol interferes with the migration and organization of brain
cells. [Journal of Pediatrics, 92(1):64-67]
2. Heavy drinking causes more clinical features of FAS than at other
times during pregnancy, according to a study in England.
[Early-Human-Development; 1983 Jul Vol. 8(2) 99-111]
3. The hippocampus is greatly affected, which leads to problems with
encoding visual and auditory information (reading and math).
[Neurotoxicology And Teratology, 13:357-367, 1991]
KNIH
Fetal Alcohol
Syndrome
Craniofacial features
KNIH
Fetal Alcohol
Syndrome
Reported Incidence rate of FAS
0.05 %
KNIH
Alcohol promotes Cancer Processing
식도
후두
KNIH
Effect of Alcohol on Heart & Blood Vessels
Alcohol
damaged heart
Alcohol misuse increases the
risk of some diseases of the
heart and blood vessels
VS
• Stroke
• Hypertension
• Peripheral vascular disease
• Cardiomyopathy
KNIH
Alcohol : inhibits heart contraction
Ca2
+
Source: Chung, M.K., and Rich, M.W. Introduction to the cardiovascular sy
stem. Alcohol Health and Research World 14(4):269-276, 1990.
KNIH
Alcohol : 사춘기 여성 LH (항체) 호르몬 분비 억제
LH(황체)호르몬? 난자가 생기고 난 뒤에 난소에서 생긴 황체에서 분비
황체호르몬은 체온을 지배하는 뇌의 체온중추에 작용하여 체온을 상승시킴 (약 2주간 지속)
IGF-1
LH (황체): +
체온 상승
난소
배란
배란 불순 및
임신이상
월경
Ethanol
LH (황체): 체온 저하
Mean menarcheal age decreased from 16.8 years to 12.7 years
during the past 67 years.
Source: Dees, W.L., et al. Alcohol’s effects on female puberty: The role of insulinlike growth factor 1. Alcohol Health & Research
World비밀,
22(3):165–169,
1998. KBS1
生老病死의
2004년 3월16일,
KNIH
기초 및 응용연구
알코올기인 간질환 및 당뇨발생
연구
1. Human Sample 이용
2. Animal model 이용
3. Cell lines 이용
KNIH
KNIH
 세포란?
60조에 이르는
우리 몸의 세포 하나 하나
핵 속 유전자
(각자 자기의 성질과 기능을
관장하는 정보가 입력)
프로그래밍
세포의 성질과 기능을 결정
"체질"
KNIH
"Angry-looking cell"
 병이란?
-- 세포의 비정상적 변화
-- 이미 유전자에 입력된 프로그램
변화의 결과.
이 세포는 그 프로그램이 변질된 세포.
초기 과학자들은 이를 흉측하게 변한
세포라 해서 "Angry-looking cell"
이라 부름
KNIH
KNIH
Cellular Responses
Signal Transduction
Pathway
Signal
Regulation of Central Dogma
DNA  RNA  Protein
KNIH
Risk Factors in Liver Injury
Alcoholic Liver Disease (ALD)
Endotoxin
(Indirect)
HCV, HBV
(Direct)
Alcohol drinking
+
?
Chronic
Normal Liver
Hepatitis
Hepatocellular
Alcoholic hepatitis
Alcoholic
carcinoma
(HCC)cirrhosis
Cirrhosis
Fatty Liver
The regulatory mechanisms underlying the interaction of
alcohol and hepatic liver injury are not clear.
KNIH
……
Alcohol
consumption
Hepatic diseases
Cardiovascular disorders
Diabetes mellitus
more than 60 different medical conditions
chronic
ethanol exposure
Lipid
accumulaion
Hepatic
steatosis
KNIH
Roles of Ethanol Consumption
Interferon Antiviral immune response
Viral replication
EtOH
(in clinical observations)
Immune system
Liver regeneration
Chronic inflammatory effect
Cytochrome p450
KNIH
Alcohol Metabolism And Cancer
Cancer
(Inactive alleles)
Nearly all Europeans
(Inactive alleles) Frequently found in
Asian populations
KNIH
ALDH2
(aldehyde dehydrogenase 2)
◦ A genetic polymorphism of ALDH2 has been characterized as
ALDH2*2, in contrast to the wild-type ALDH2*1.
◦ This polymorphism is seen in about half the population of
East Asian countries (Chao et al., 2000; Takeshita et al., 1993).
◦Acetaldehyde is metabolized very slowly in people who have
ALDH2*2, as the mutated ALDH2 lacks acetaldehyde
metabolizing activity.
KNIH
Liver
Hepatocytes
Apoptosis
Necrosis
Kupffer cells
Inflammation
immune response
Stellate cells
Fibrosis
Ischemia
Endothelial cells
Altered
Regeneration
Gene Exp.
Liver injury
Acute hepatitis
Chronic hepatitis
(Steatosis)
Cirrhosis
Fibrosis
Hepatocellular
carcinoma(HCC)
KNIH
The Structure of the liver’s functional units,
or lobules
100,000 lobules
Blood enters the lobules through
branches of the portal vein and
hepatic artery
Flow small channels
called sinusoids
Hepatocytes : Remove toxic
substances, including alcohol,
from the blood
then exits the lobule through the
central vein
KNIH
Progression of liver injury in alcoholic fibrosis
EtOH
SECs
?
Kupffer cells
Stellate cells
Fibrosis
ECM & TGF-
Retinol
Source: Friedman, S.L. Scarring in alcoholic liver disease: New insights and emerging therapies. Alcohol Health & Research
World 21(4):310–316, 1997.
Effects of Alcohol Consumption
on Oxygen use
KNIH
Alcohol Consumption
Indirect
Immune-cells
Kupffer cells
Various signaling mole.
& stimulatory mole.
(e.g., prostaglandin E2)
Alcohol
Oxidation
ADH
Direct
CYP2E1
ALDH2
Acetaldehyde
Oxidation
NADH Oxidation
(in mitochondria)
Acetaldehyde,
Acetate, or
NAD+
Stimulate Hepatocytes
Oxidation & reduction
Liver oxygen use
Effects of Alcohol Consumption
on Oxygen use
KNIH
Blood has high
oxygen
O2
O2
O2
(+)
Alcohol consumption
O2
Blood has less
oxygen
Effects of Alcohol Consumption
on ATP levels
Nutrients
(carbohydrates, proteins, and fats)
Apoptosis
Oxygen
Hepatocytes
deficient
?
ATP
Alcohol
consumption
Cell’s survive
Toxic compound
Damage of cell
structure and
complex molecules
(Acetaldehyde, ROS,
peroxynitrite, hydroxylethyl
radical, and lipid peroxides)
KNIH
KNIH
Link between Endotoxins release and Liver injury
Hepatology 2006 43:989-1000
4
LPS, lipoteichoic acid,
peptidoglycan (PGN), loxoribine
3
TLR4
+
DPI
EtOH +
TLR ligands
Lieber-DeCarli diet
1
2
fed
?
C57BL6/J mice
Liver Injury
(Steatosis, liver weight, AST,
TLR1,2,4,6,7,8, and 9)
Source: Wheeler, M.D. Endotoxin and kupffer cell activation in alcoholic liver disease. Alcohol Research & Health
27(4):300–306, 2003.
Oxidative
stress
KNIH
Alcohol Metabolism and Cancer
Cancer
(Inactive alleles)
Nearly all Europeans
(Inactive alleles) Frequently found in
Asian populations
KNIH
Toxic Products resulting from the
breakdown, or metabolism of Alcohol
hydroxyethyl radical (HER), malondialdehyde (MDA), 4–hydroxy–2–nonenal (HNE)
KNIH
Gene A
Gene B
Environmental
Factor 1
Free radical
Environmental
generation
Factor 2
MPP+
viral agents
rural living
wood mills
well water
Mn, cyanide
Pesticides
Smoking
Caffeine
Anti-oxidant
defense
DISEASE!
mechanisms
KNIH
Apoptosis & Necrosis
(수포)
Source: Goodlett, C.R., and Horn, K.H. Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol
Research & Health 25(3):175–184, 2001.
KNIH
Animal Models on Liver injury and Diabetes
Ad-HBx
LPS/GalN
ConA, CCl4
STZ
EtOH
Metabolisms
?
KNIH
Effect of ethanol on innate antiviral pathways
and HCV replication in human liver cells
C. R. Plumlee et al., 2005 Virology. J. 2: 89
HCV Infection
Therapy
IFNs
참이슬
Riva.
Chronic Hepatitis C
참이슬
KNIH
Pathogenesis of NAFLD
KNIH
Obesity & NIDDM
 Hyperinsulinemia
Genetic
 Hyperglycemia
NIDDM
?
 Insulin resistance
Steatosis
 Hypertriglycemia
 Mild obesity
environments
Sex
Alcohol
100% penetrance of diabetes in male OLETF rats of 25 weeks
KNIH
Obesity & NIDDM
Non-insulin dependent diabetes mellitus (NIDDM)
: a metabolic disorder characterized by abnormal glucose metabolism
600-650 g : most of rats show type 2 diabetes
Obesity
3-5
folds
Below 600 g : most of rats don’t
show type 2 diabetes
10-50
folds
Many Diabetes
diseases
KNIH
퇴행성관절염
담석증
KNIH
Obesity & NIDDM
Western People
Korean, Japanese, etc
Obesity
Less Obesity
?
Type 2 Diabetes
Many diseases
much more
susceptible to
obesity
KNIH
Major cause factors of type 2 diabetes
Genetic
factor
Environmental
factor
Obesity
?
Alcohol
By car, computer, excess food, etc
Searching diabetogenic genes
responsible for obesity
Identify the gene responsible for
type 2 diabetes with mild obesity
Type 2 Diabetes
Develop new medicines
Two people with Diabetogenic gene,
but environmental factor?
KNIH
그렇게 술 마시니
살이 찌고 당뇨가
오지…
맨날 주식하다 알
거지 된 너도 참….
KNIH
Alcohol
Cell Death and
Survival
Mechanisms
ER, mito, ROS
Oxidant Stress
and
Inflammation
Metabolism,
Cancer, and
Genetics
GSH, cytokines
HCV, HBV, ALDH
Liver diseases
Fibrosis, Steatosis,
Cirrhosis, HCC
Stellate Cell Biology
and Fibrosis
NKT, macrophage,
Steatosis, fibrosis
Pancreas diseases
Pancreatitis,
Pancreatic cancer
Diabetes & obesity
KNIH
Heat shock, oxygen radicals,
A a analogs, heavy metal etc
Alcohol
Ceramide
Akt
GSK3
Apoptosis
Homocystein
ER stress
ROS
In pancreatitis
m
Palmitic
acid
Myristic acid
Cancer
cells
HSP70
ATP
Necrosis
Ca2+
Cyt C
Caspase
Steatosis
Cirrhosis
Fibrosis
Apoptosis
HCC
KNIH
ACKNOWLEDGEMENT
S
국립보건연구원
생명의과학센터 난치성질환
Hyun Jung Lee, PhD
Sung Hee Lee, Ms
Yeo Kyung Oh, Ms
미국 NIH/NIAAA
Bin Gao, MD., PhD (section Chief)
성균관대학교 의과대학
Lee, Myeong Sik, MD., PhD (교수)
생명공학원
Ji Yeon Kim, PhD
Eun Hyun Song, Ms
Jeong Min Kim, Ms
Yu, DAE-Yeul, PhD
중앙대학교
Kyung Hee Choi, Ph.D (교수)