Post on 08-Nov-2014
transcript
Diet and Chronic Liver Disease:A Nutrigenomics Perspective
Johana TitusDepartment of Nutrition
Faculty of Medicine University of Indonesia
Diet-chronic diseases
• Hippocrates
- The importance of a good diet for preventionof disease
- Imbalance of lifestyle and diet with the body’
2
- Imbalance of lifestyle and diet with the body’humors resulted in illness
Halsted CH. Am J Clin Nutr 1998; Vol. 67: 192-6
• Epidemiological studies
– Associations between food and/or beverageswith chronic diseases have long beendocumented
Burton H and Stewart (2004).
Nutrient-gene-chronic diseases
• Epidemiological studies- Absence of genetic knowledge may result in
erroneous scientific conclusions
• Nutrigenomics technologies enable us to find
3
• Nutrigenomics technologies enable us to findout:- The basis of food’s functional interactions with
the genome at the molecular, cellular &systemic levels
- Genetic variations and epigenetic events whichalter requirements for, and responses to,nutrients
Burton H and Stewart (2004).
Nutrigenomics perspective
Nutrients (dietary signals )
Transcription factors
Genes expression
4
Genes expression
mRNA
Proteins expression dietary
signature
Metabolites production
Muller M and Kersten S. (2003)
Nutrient Compound Transcriptionfactor
Macronutrients
Fats Fatty acids PPARs, SREBPs,
Table 1Transcription-factor pathways mediating nutrient–geneinteractions (1)
5
Fats Fatty acidsCholesterol
PPARs, SREBPs,LXR, HNF4,ChREBPSREBPs, LXRs,FXR
Carbohydrates Glucose USFs, SREBPs,ChREBP
Proteins Amino acids C/EBPs
Muller M and Kersten S. (2003)
Nutrient Compound Transcriptionfactor
Micronutrients
Vitamins Vitamin A RAR, RXR
Table 1Transcription-factor pathways mediating nutrient–geneinteractions (2)
6
Vitamins Vitamin AVitamin DVitamin E
RAR, RXRVDRPXR
Minerals CalciumIronZinc
Calcineurin/NF-ATsIRP1, IRP2MTF1
Other foodcomponents
FlavonoidsXenobiotics
ER, NF.B, AP1CAR, PXR
Muller M and Kersten S. (2003)
Transgenic animal cell models
7
Muller M and Kersten S. (2003)
Transcriptomics
uses microarrays to understand:
How nutritional exposure influences
8
How nutritional exposure influences
gene expression on a genomic scale.
Burton H and Stewart (2004).
Proteomics
using mass spectrometric techniques to
investigate different protein expressions
9
under different conditions and/or with
different underlying pathologies.
Burton H and Stewart (2004).
Metabolomics(or metabonomics)
To examine global patterns of metabolites
present in the cell or in body fluids in
10
present in the cell or in body fluids in
response to specific dietary exposures
by HPLC or other separation techniques
Burton H and Stewart (2004).
Genomics tools
All of these “-omics tools” have beenused to study :
– in detail the molecular responses to food
11
– in detail the molecular responses to foodsubstances or the early stages of disease incommon diet-related conditions
– Who will succumb to disease and who willrespond to dietary modification?
Burton H and Stewart (2004).
Ultimately, Nutrigenomics :
Application of genomics in nutrition scienceshould allow us to provide :
Dietary interventional strategies
12
Dietary interventional strategies
to recover normal homeostasis
and
to prevent dietary-related diseases
Burton H and Stewart (2004).
Diet-related disease
Genomics tools (Nutrigenomics)Have been used for detailed studies on thebody’s molecular responses to foodsubstances or the early stages of disease in
13
substances or the early stages of disease incommon dietary-related conditions, suchas:
• Dietary-related Heart Disease• Diet relation to several Chronic Disease;
Hypertension, Diabetes, Obesity,cancer, Chronic liver disease, etc.
Burton H and Stewart (2004).
The Liver
• Plays a key regulatory role in themetabolism of human body
• Host defense; a complex interaction
14
• Host defense; a complex interactionbetween the Kupffer cell (KC) andhepatocyte;
KC, activated by bacterial product fromthe portal vein and the systemiccirculation scavenging of bacterial
Meijer et. al (1996)
Acute state
release mediators of inflamation(TNF, IL-1, IL-6, IL-8, IFN, ROS, NO & PAF)
The Liver and inflammation
15
KC inflammatory response↑ REE dan ↑Acute phase protein
Proinflammatory stressMetabolic stress
Meijer et. al (1996)
Gene expression patterns inmetabolic and proinflammatory stress
16Whitney et al (2003)
Proinflammatory-tissue injury
An uncontrolled release of inflammatorymediators;
• TNF and IL-1 induce the expression ofELAM-1 dan ILAM-1 on endothelial cells,
17
ELAM-1 dan ILAM-1 on endothelial cells,induce procoagulant state
•Activated neutrophils through adhesionproteincytotoxic radical & proteolyticenzim
Endothelial damage
Meijer et. al (1996)
Mediators-Prooxidant-Liver Failure
Expression of tissue factor and adhesion of platelets,complement products, and fibrin to injured wall
microthrombus
Disturbance Oxygen at cellular level
18
Tissue necrosis
Release cytotoxic mediator stiff Neutrophils
Reducing the liver blood flow
Liver failure Chronic liver disease
Meijer et. al (1996)
Prooxidant-Fibrogenesis
Tissue necrosis Release cytotoxic mediator
Reactive Oxygen free radical
19
Active toxic metabolites
Superoxid, H2O2, Hydroxyl radical
Damage the cellular membrane + the envelope oforganell (peroxidation PUFA within Phospholipis
structure of the membrane)
Meijer et. al (1996)
pathogenesis of Chronic liver disease
20
• The burden of chronic liver disease is expected to riseowing to increasing rates of alcoholism, hepatitis B andC prevalence as well as obesity-related fatty liverdisease.
• Up to 80% of HCV-infected individuals fail to eliminatethe virus acutely and progress to chronic HCV infection.
Chronic liver disease CLD)
21
• Up to 80% of HCV-infected individuals fail to eliminatethe virus acutely and progress to chronic HCV infection.
• Continuous inflammation and hepatocyte regenerationin the setting of chronic hepatitis and subsequentprogression to cirrhosis is thought to lead tochromosomal damage and possibly to initiate hepaticcarcinogenesis
• Fibrotic progression in HCV-infectedpatients is markedly variable.
The rate of fibrotic progression
22
• It is not clear whether influenced by:
- Age at the time of infection
- Sex, HCV genotype
- Environmental factor; lifestyle and food
• Nutrition is an environmental factor involved in thedevelopment and progression of metabolic disorderssuch as chronic liver diseases
• A number of studies have been on the effect of humanfoods on the nuclear transcription factors of hepatitis
Nutrigenomics and Chronic liverdisease
23
foods on the nuclear transcription factors of hepatitisvirus
• Several studies have hypothesized that plant phenolsmight protect cellular DNA, lipids and proteins fromfree radical- mediated damage in vivo.
• In the Japanese population,habitual coffee drinking maybe associated with reduced risk of HCC.
• Qing L et.al. (2010) 3 nutrients (β-carotene,vitamin D2, and linoleic acid) and severalPUFAs, especially AA, DHA, and EPA, are ableto inhibit HCV-RNA replication in a cell culturesystem .
Nutrigenomics Therapyof Hepatisis C Virus
24
• PUFAs Mechanism of actions:o Changing the gene expression of PPAR- and SREBPo Suppressing expression of mRNAs encoding key
metabolic enzymeso Suppressing hepatic lipogenesis andtriglyceride
synthesis, secretion, and tissue’s accumulation.
• Lee et.al. (2010) Two coffee’s diterpenes(kahweol and cafestol) were found to havehepatoprotective properties towards CCl4-induced liver damage in mice
Hepatoprotective and antioxidant effectsof the coffee
25
• Mechanism of actions :o Prevention of serum levels’ SGOT/SGPT increaseo Reduction of lipid peroxidation in the liver (dose-
dependent)o Significant decrease in CYP2E1, the major isozyme
involved in CCl(4) bioactivationo Antioxidant effects
Plant phenols
In vitro :
Possess strong antioxidant activities
In vivo :
ANTIOXIDANTS IN COFFEE
26
In vivo :
Hypothesized of having protective effectson cellular DNA, lipids, and proteins.
Conclusion
• Nutrigenomics provides tools to study nutrient’seffects on molecular and genetic levels anddevelop diets which are potentially able toprevent/restrict the spreading of chronicdiseases, incl. chronic liver disease
27
diseases, incl. chronic liver disease
• Individually tailored diets with specificnutrients adjusted to patient’s genome profileare important features in future nutritionaltreatments of chronic liver disease
Diet hati
Bagaimana pengaruh Diet Hati kitaterhadap genome,
Dapatkah Diet Hati menghambat
28
Dapatkah Diet Hati menghambatprogresifitas kerusakan hepatosit atau
sebaliknya ?
BAHAS PADA KESEMPATAN LAIN
References (1)
• Burton H and Stewart A NUTRIGENOMICS Report of a workshophosted by The Nuffield Trust and organized by the Public HealthGenetics Unit on 5 February 2004.
• Halsted CH. Clinical Nutrition education-relevance and rolemodels. Am J Clin Nutr 1998; Vol. 67: 192-6
29
models. Am J Clin Nutr 1998; Vol. 67: 192-6
• Zeisel SH. Nutrigenomics and metabolomics will change clinicalnutrition and public health practice: insights from studies ondietary requirements for choline. Am J Clin Nutr September 2007;Vol. 86 (3): 542-548.
• Gomaa AI, Khan SA, Toledano MB, Waked I, and Taylor-RobinsonSD. Hepatocellular carcinoma: Epidemiology, risk factors andpathogenesis World J Gastroenterol. 2008 July 21; 14(27): 4300–4308.
• Qing L, Bengmark S, Shen Q. Nutrigenomics Therapy of Hepatisis CVirus Hepatosteatosis BMC Gastroenterology 2010, 10:49
References (2)
30
Virus Hepatosteatosis BMC Gastroenterology 2010, 10:49
• Antioxidance in Coffee search from Site Search by Pico Search;http//www.picosearch.com/cgi-bin/index. June 27: 2010
• Tanaka K, Hara M, Sakamoto T, Higaki Y, Mizuta T, Eguchi Y, et all.Inverse association between coffee drinking and the risk ofhepatocellular carcinoma: a case-control study in Japan. Cancer SciFebruary 2007; vol. 98 (2): 214–218
• Gomaa A. Khan S. Toledano, M. Taylor-Robinson, S. Hepatocellularcarcinoma: Epidemiology, risk factors and pathogenesis. World JGastroenterol. 2008 July 21; 14(27): 4300-4308.
• Lee KJ, Choi JH, Jeong HG. Hepatoprotective and antioxidant effectsof the coffee diterpenes kahweol and cafestol on carbon tetrachloride-induced liver damage in mice. Food Chem Toxicol. 2007Nov;45(11):2118-25. Epub 20
References (3)
31
Nov;45(11):2118-25. Epub 20
• Meijer C, Statuius Muller MG, van Leeuwen PAM. The Liver in TheInduction and Regulation of the Acute Stress Response. In Vincent JLed. Update in Intensive Care and Emergency Medicine. AcuteCatabolic State. 1996 Springer: 129-140
• Muller M and Kersten S. Nutrigenomics: Goals and strategies. NatureReview/ Genetic. 2003; vol 4: 315-321.
32