Diet and Chronic Liver Disease: A Nutrigenomics Perspective

Johana Titus Department of Nutrition Faculty of Medicine University of Indonesia

Diet-chronic diseases
Hippocrates
The importance of a good diet for prevention of disease 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 beverages with chronic diseases have long been documented 2
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 out:

The basis of foods functional interactions with the genome at the molecular, cellular & systemic levels Genetic variations and epigenetic events which alter requirements for, and responses to, nutrients

Burton H and Stewart (2004).

Nutrigenomics perspective
Nutrients (dietary signals ) Transcription factors Genes expression mRNA Proteins expression Metabolites production
Muller M and Kersten S. (2003) 4

dietary signature

Table 1 Transcription-factor pathways mediating nutrientgene interactions (1) Nutrient Macronutrients Fats Fatty acids Cholesterol PPARs, SREBPs, LXR, HNF4, ChREBP SREBPs, LXRs, FXR USFs, SREBPs, ChREBP C/EBPs
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Compound

Transcription factor

Carbohydrates Proteins
Muller M and Kersten S. (2003)

Glucose Amino acids

Table 1 Transcription-factor pathways mediating nutrientgene interactions (2) Nutrient Micronutrients Vitamins Vitamin A Vitamin D Vitamin E Calcium Iron Zinc Flavonoids Xenobiotics RAR, RXR VDR PXR Calcineurin/NFATs IRP1, IRP2 MTF1 ER, NF.B, AP1 CAR, PXR
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Compound

Transcription factor

Minerals

Other food components

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 gene expression on a genomic scale.

Burton H and Stewart (2004).

Proteomics
using mass spectrometric techniques to investigate different protein expressions 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 response to specific dietary exposures by HPLC or other separation techniques

Burton H and Stewart (2004).

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Genomics tools
All of these -omics tools have been used to study :
in detail the molecular responses to food substances or the early stages of disease in common diet-related conditions Who will succumb to disease and who will respond to dietary modification?
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Burton H and Stewart (2004).

Ultimately, Nutrigenomics :
Application of genomics in nutrition science should allow us to provide :

Dietary interventional strategies to recover normal homeostasis and to prevent dietary-related diseases
Burton H and Stewart (2004). 12

Diet-related disease
Genomics tools (Nutrigenomics) Have been used for detailed studies on the bodys molecular responses to food substances or the early stages of disease in common dietary-related conditions, such as: Dietary-related Heart Disease Diet relation to several Chronic Disease; Hypertension, Diabetes, Obesity, 13 cancer, Chronic liver disease, etc.

Burton H and Stewart (2004).

The Liver
Plays a key regulatory role in the metabolism of human body Host defense; a complex interaction between the Kupffer cell (KC) and hepatocyte; KC, activated by bacterial product from the portal vein and the systemic circulation scavenging of bacterial
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Meijer et. al (1996)

The Liver and inflammation

Acute state release mediators of inflamation (TNF, IL-1, IL-6, IL-8, IFN, ROS, NO & PAF)

KC

inflammatory response REE dan Acute phase protein Proinflammatory stress Metabolic stress
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Meijer et. al (1996)

Gene expression patterns in metabolic and proinflammatory stress

Whitney et al (2003)

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Proinflammatory-tissue injury
An uncontrolled release of inflammatory mediators; TNF and IL-1 induce the expression of ELAM-1 dan ILAM-1 on endothelial cells, induce procoagulant state Activated neutrophils through adhesion protein cytotoxic radical & proteolytic enzim Endothelial damage
Meijer et. al (1996)

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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 Tissue necrosis Release cytotoxic mediator stiff Neutrophils Reducing the liver blood flow Liver failure Chronic liver disease
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Meijer et. al (1996)

Prooxidant-Fibrogenesis
Tissue necrosis Release cytotoxic mediator Reactive Oxygen free radical Active toxic metabolites Superoxid, H2O2, Hydroxyl radical Damage the cellular membrane + the envelope of organell (peroxidation PUFA within Phospholipis structure of the membrane)
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Meijer et. al (1996)

pathogenesis of Chronic liver disease

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Chronic liver disease CLD)

The burden of chronic liver disease is expected to rise owing to increasing rates of alcoholism, hepatitis B and C prevalence as well as obesity-related fatty liver disease. Up to 80% of HCV-infected individuals fail to eliminate the virus acutely and progress to chronic HCV infection. Continuous inflammation and hepatocyte regeneration in the setting of chronic hepatitis and subsequent progression to cirrhosis is thought to lead to chromosomal damage and possibly to initiate hepatic carcinogenesis
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The rate of fibrotic progression

Fibrotic progression in HCV-infected patients is markedly variable. It is not clear whether influenced by: - Age at the time of infection - Sex, HCV genotype - Environmental factor; lifestyle and food
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Nutrigenomics and Chronic liver disease

Nutrition is an environmental factor involved in the development and progression of metabolic disorders such as chronic liver diseases A number of studies have been on the effect of human foods on the nuclear transcription factors of hepatitis virus Several studies have hypothesized that plant phenols might protect cellular DNA, lipids and proteins from free radical- mediated damage in vivo. In the Japanese population,habitual coffee drinking may be associated with reduced risk of HCC.
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Nutrigenomics Therapy of Hepatisis C Virus

Qing L et.al. (2010) 3 nutrients (-carotene, vitamin D2, and linoleic acid) and several PUFAs, especially AA, DHA, and EPA, are able to inhibit HCV-RNA replication in a cell culture system . PUFAs Mechanism of actions:
o Changing the gene expression of PPAR- and SREBP o Suppressing expression of mRNAs encoding key metabolic enzymes o Suppressing hepatic lipogenesis andtriglyceride synthesis, secretion, and tissues accumulation.
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Hepatoprotective and antioxidant effects of the coffee

Lee et.al. (2010) Two coffees diterpenes (kahweol and cafestol) were found to have hepatoprotective properties towards CCl4induced liver damage in mice Mechanism of actions :
o Prevention of serum levels SGOT/SGPT increase o Reduction of lipid peroxidation in the liver (dosedependent) o Significant decrease in CYP2E1, the major isozyme involved in CCl(4) bioactivation o Antioxidant effects
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ANTIOXIDANTS IN COFFEE
Plant phenols In vitro : Possess strong antioxidant activities In vivo : Hypothesized of having protective effects on cellular DNA, lipids, and proteins.

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Conclusion
Nutrigenomics provides tools to study nutrients effects on molecular and genetic levels and develop diets which are potentially able to prevent/restrict the spreading of chronic diseases, incl. chronic liver disease Individually tailored diets with specific nutrients adjusted to patients genome profile are important features in future nutritional treatments of chronic liver disease
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Diet hati
Bagaimana pengaruh Diet Hati kita terhadap genome, Dapatkah Diet Hati menghambat progresifitas kerusakan hepatosit atau sebaliknya ?

BAHAS PADA KESEMPATAN LAIN

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References (1)
Burton H and Stewart A NUTRIGENOMICS Report of a workshop hosted by The Nuffield Trust and organized by the Public Health Genetics Unit on 5 February 2004. Halsted CH. Clinical Nutrition education-relevance and role models. Am J Clin Nutr 1998; Vol. 67: 192-6 Zeisel SH. Nutrigenomics and metabolomics will change clinical nutrition and public health practice: insights from studies on dietary requirements for choline. Am J Clin Nutr September 2007; Vol. 86 (3): 542-548.

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References (2)
Gomaa AI, Khan SA, Toledano MB, Waked I, and Taylor-Robinson SD. Hepatocellular carcinoma: Epidemiology, risk factors and pathogenesis World J Gastroenterol. 2008 July 21; 14(27): 43004308. Qing L, Bengmark S, Shen Q. Nutrigenomics Therapy of Hepatisis C 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 of hepatocellular carcinoma: a case-control study in Japan. Cancer Sci February 2007; vol. 98 (2): 214218
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References (3)
Gomaa A. Khan S. Toledano, M. Taylor-Robinson, S. Hepatocellular carcinoma: Epidemiology, risk factors and pathogenesis. World J Gastroenterol. 2008 July 21; 14(27): 4300-4308. Lee KJ, Choi JH, Jeong HG. Hepatoprotective and antioxidant effects of the coffee diterpenes kahweol and cafestol on carbon tetrachlorideinduced liver damage in mice. Food Chem Toxicol. 2007 Nov;45(11):2118-25. Epub 20 Meijer C, Statuius Muller MG, van Leeuwen PAM. The Liver in The Induction and Regulation of the Acute Stress Response. In Vincent JL ed. Update in Intensive Care and Emergency Medicine. Acute Catabolic State. 1996 Springer: 129-140 Muller M and Kersten S. Nutrigenomics: Goals and strategies. Nature Review/ Genetic. 2003; vol 4: 315-321.
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