Liver

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Non-Alcoholic Fatty Liver Disease (NAFLD) A new
consequence of the obesity epidemic.
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Outline

• NAFLD
• 2. Some of the questions being pursued
• 3. Current ideas and directions

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Non-Alcoholic Fatty Liver Disease (NAFLD)
Fatty liver (Steatosis)
Normal liver
Steatohepatitis - inflammation - fibrosis
Cirrhosis
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NAFLD
1. Most common of all liver disorders. 2. Most
frequent cause of chronic liver disease. 3.
Affects 3-20 of general population. 4. Present
in up to 75 of individuals with obesity,
type 2 diabetes. 5. Present in 3 of children and
gt50 of obese children.
Fatty Liver Disease NASH and Related
Disorders Blackwell Publishing, 2005
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The Brief History of NAFLD

• 1979 8 papers published
• 1998 First NIH conference
• 1999 First Clinical Trials
• 2002 60 papers published
• Release of first book on NAFLD/NASH
• 2005 354 papers published

Fatty Liver Disease NASH and Related
Disorders Blackwell Publishing, 2005
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Non-Alcoholic Fatty Liver Disease (NAFLD)
Fatty liver (Steatosis)
?
?
Steatohepatitis - inflammation - fibrosis
Cirrhosis
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Two-hit Hypothesis
Fatty Liver
Diet FFA
Burned VLDL-TG
1st Hit
Susceptibility
Oxidative Stress
2nd Hit
Toxins
Inflammatory Molecules
Damaged Liver
Donnelly et al. J. Clin. Invest. 113 1343,
2005 Day and James. Gastroenterol. 114 842, 1998
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Addition to the Two-hit Hypothesis
Type ? Saturated vs.
Unsaturated
Fatty Liver 1st Hit
Susceptible
Oxidative Stress
2nd Hit
Toxins
Inflammatory Molecules
Damaged Liver
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Subject Characteristics
Collaboration with UT Southwestern
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Hypothesis
Type ? Saturated vs.
Unsaturated
Fatty Liver 1st Hit
Susceptible
Oxidative Stress
2nd Hit
Toxins
Inflammatory Molecules
Damaged Liver
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Relationship between saturated fatty acids and
liver injury in morbidly obese subjects
Liver Injury
Normal
Amount of saturated lipids in liver
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Dietary models of hepatic steatosis
Endocrinology 147943, 2006
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Increased susceptibility to lipopolysaccharide in
steatosis characterized by increased saturated
fatty acids
Sat FA - -
- -
Steatosis -
-
Liver Injury
Endocrinology 147 943, 2006
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Two-hit Hypothesis 1
Fatty Liver
1st Hit
Susceptible
Saturated Fats
Oxidative Stress
2nd Hit
Toxins
Inflammatory Molecules
Damaged Liver
Damage
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Non-Alcoholic Fatty Liver Disease (NAFLD)
Fatty Liver NASH Fibrosis Cirrhosis
Hepatocyte apoptosis increased in patients with
non-alcoholic steatohepatitis (NASH).
Canbay et al. Hepatol. 39 273, 2004
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Saturated fatty acids induce apoptosis in liver
cells
6 Hours 16 Hours
Am. J. Physiol. (In Press)
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Ratio of saturated to unsaturated fatty
acids determines degree of apoptosis in liver
cells
16 Hours
Am. J. Physiol. (In Press)
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Two-hit Hypothesis 1
Fatty Liver
1st Hit
Susceptible
Saturated Fats Unsaturated Fats
Oxidative Stress
2nd Hit
Toxins
Inflammatory Molecules
Damaged Liver
Apoptosis
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Fatty Liver
2nd Hit
2nd Hit
Sat FA
Liver Damage
Liver Damage
Apoptosis
Hepatocyte Mass
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Fatty Liver Saturated Lipids
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Metabolism of and signals generated by saturated
fatty acids
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Liver Damage
?
Apoptosis
Fibrosis
?
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Therapeutic Arm Application Arm
Plant-based compounds UT Southwestern - Dr.
Jorge Vivanco Denver Health Taurine - Dr. Ken
Maclean
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Acknowledgments
Pagliassotti Lab Collaborators Rosie
Wei Dong Wang Farran Peterson Jennifer
Kemp Jon Gonzales Kyle Pfaffenbach Chris Mulligan
Jorge Vivanco Ken Maclean Dan Bessesen Tracy
Horton
Funding Support NIH (DK047416, DK072017)
American Diabetes Association, Lillian Fountain
Smith Endowment
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