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