1. Genetics and epigenetics of NAFLD and NASH
Sameh Lashen
Lecturer of Hepatology
University of Alexandria

3. Epigenetics
Epigenetics is the study of heritable changes in gene expression (without changes to the underlying DNA sequence) i.e. A change in phenotype (Product), without a change in genotype.
Epigenetic change is a regular and natural occurrence but can also be affected by several factors including age, the environment, lifestyle, and disease state.

6. Non-coding mRNAs

7. Environmental factors
Genetic changes
Environmental factors
Non-coding miRNAs

9. Natural History of NAFLD (~8-13 ys)
Simple Steatosis
F1-2 fibrosis
12-40%
5-15%
0-50%
1-3%
Sever fibrosis F3
HCC

10. Natural History of NAFLD (~8-13 ys)
Simple Steatosis
F1-2 fibrosis
12-40%
13%
5-15%
0-50%
1-3% 8%
Sever fibrosis F3
HCC

11. Natural History of NAFLD (~8-13 ys)
Simple Steatosis
F1-2 fibrosis
12-40%
13%
5-15%
0-50%
1-3% 8%
Sever fibrosis F3
?? %
??%
HCC

12. 1st degree relatives

13. Gastroenterology 2015
52%

14. Gastroenterology 2015
50%

15. Heritability of NAFLD
Overall, these data suggest that approximately half of hepatic fat content variability is explained by genetic and epigenetic factors, which also determine the risk of metabolic disease and hepatic fibrosis.

16. Pathogenesis of NAFLD

17. Gene loci associated with NAFLD susceptibility
PNPLA3 (Chr 22)
Normal function
Code for protein involved in lipid hydrolysis (hydrolase activity for TG)
Mutation changes
Loss of function [ IsoleucinMethionin at 148]
Molecular effect
Entrapment of TG inside hepatocytes and stellate cells hepatic injury and fibrosis progression
Clinical impact
In homozygous, NAFLD progression and X10 increase in HCC risk

18. Gene loci associated with NAFLD susceptibility
Trans-membrane 6 superfamily member 2 (TM6SF2)… (Chr 19)
Normal function
Protein which incorporates Apo-lipoprotein B100 +TG into VLDV push outside the liver
Mutation changes
Loss of function
Molecular effect
Entrapment of TG inside the liver
Low circulating lipoproteins
Clinical impact
NAFLD progression
Low risk of cardiovascular diseases

19. Gene loci associated with NAFLD susceptibility
J.Hepatol 2017
Gene
Membrane bound O-acyl-transferase domain containing 7 (MBOAT7)
Normal function
Protein involved in phosphatidylinositol supply to hepatocytes
Mutation changes
Loss of function
Molecular effect
reduced levels of phosphatidyl-inositol containing arachidonic acid in hepatocytes and the circulation
Clinical impact
Higher risk of NAFL , NASH and fibrosis.
Higher risk of progression to HCC.

20. Insulin resistance
Role of IR in NAFLD pathogenesis is well established
Common polymorphisms of genes involved in the insulin signaling pathway has been associated with progression of fibrosis.

21. Epigenetic factors in the pathogenesis of NAFLD
Epigenetic changes are relatively stable alterations that can be transmitted to progeny through cell division, thereby explaining the effect of environmental factors on phenotype, and part of the disease which is not explained by common genetic variations.
Non-coding miRNAs

22. Epigenetic factors in the pathogenesis of NAFLD
A classic demonstration of the role of epigenetic factors in modulating an individual’s susceptibility to NAFLD is represented by the effect of intrauterine exposure to high-fat diet (HFD) in inbred mouse strains

23. Epigenetic factors in the pathogenesis of NAFLD
This not only worsen visceral fat accumulation and insulin resistance after birth, but it also results in more severe hepatic fat accumulation and the development of NASH.

24. Epigenetic factors in the pathogenesis of NAFLD
The same effect occurs in human where liver damage due to fetal exposure to high fat diet interferes with
cell cycle regulation in hepatocytes because of p21 induction by methylation.

25. Epigenetic factors in the pathogenesis of NAFLD
In line with these data, increased hepatic methylation of PPAR-γ, involved in mitochondrial biogenesis of enzymes involved in oxidative phosphorylation insulin resistance, and NAFLD progression.

26. Epigenetic factors in the pathogenesis of NAFLD
Hypo-methylation of fibrogenic TGF-b1 and PDGF-a has been associated with rapid progression of NAFLD

27. Epigenetic factors in the pathogenesis of NAFLD
Spontaneous development of NASH due to heightened
lipogenesis and impaired lipid secretion, and subsequent
progression to HCC

28. Clinical and translational implications
Understanding the genetic and epigenetic alterations in NAFLD has led to:
Understanding the variation in disease phenotypes.
Better risk stratification for disease progression,
Development of new diagnostic/prognostic biomarkers,
Development of new drugs to personalize and improve the quality of care for patients.

29. Clinical and translational implications
Understanding the genetic and epigenetic alterations in NAFLD has led to:
Understanding the variation in disease phenotypes.
Better risk stratification for disease progression,
Development of new diagnostic/prognostic biomarkers,
Development of new drugs to personalize and improve the quality of care for patients.
HCC risk score in NAFLD based on a combination of genetic risk variants (in PNPLA3, TM6SF2, and MBOAT7) and clinical risk factors.
Fibrosis progression score based on IFNL3 gene polymorphism + clinical factors.

30. Clinical and translational implications
Understanding the genetic and epigenetic alterations in NAFLD has led to:
Understanding the variation in disease phenotypes.
Better risk stratification for disease progression,
Development of new diagnostic/prognostic biomarkers,
Development of new drugs to personalize and improve the quality of care for patients.
To date, No consensus recommendation guidelines about pharmacologic therapy for NAFLD

31. Clinical and translational implications
Understanding the genetic and epigenetic alterations in NAFLD has led to:
Understanding the variation in disease phenotypes.
Better risk stratification for disease progression,
Development of new diagnostic/prognostic biomarkers,
Development of new drugs to personalize and improve the quality of care for patients.
Emerging data suggests that genetic background may determine the response to lifestyle modification.

32. Clinical and translational implications
Understanding the genetic and epigenetic alterations in NAFLD has led to:
Understanding the variation in disease phenotypes.
Better risk stratification for disease progression,
Development of new diagnostic/prognostic biomarkers,
Development of new drugs to personalize and improve the quality of care for patients.
For example, reduction in liver fat and liver enzymes in response to weight loss was larger in subjects homozygous for
the PNPLA3.

33. Clinical and translational implications
Understanding the genetic and epigenetic alterations in NAFLD has led to:
Understanding the variation in disease phenotypes.
Better risk stratification for disease progression,
Development of new diagnostic/prognostic biomarkers,
Development of new drugs to personalize and improve the quality of care for patients.
More recently, down-regulation of the mutated PNPLA3 protein holds promise for the treatment of liver diseases associated with steato-hepatitis.

35. Thank You