KINESIOL 1Y03 Chapter Notes - Chapter 12: Sleep Apnea, Factor V Leiden, Oxidative Stress
22 Jun 2018
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The genetics of NAFLD/NASH
Hepatic steatosis = “pathological definition of the presence of fat vesicles, predominantly
triglycerides, accumulating within hepatocytes”
NAFLD = “the presence of hepatic steatosis as part of the metabolic syndrome of obesity,
insulin resistance / T2DMand dyslipidaemia”
NASH = “rare complication of NAFLD, where inflammation of the liver has occurred”
-Fluctuating AST and ALT elevation
-Characteristic histological appearance in the absence of alcohol Hx
-Ballooning of fat droplets with chicken-wire fibrosis between hepatocytes
-Poor prognosis
Causes of fatty liver can be primary or secondary:
Primary = associates with obesity, T2DM, dyslipidaemia
Secondary = alcohol, drugs (steroids, amiodorone, HAART), Hep C, parenteral nutrition
Epidemiology of NAFLD
= leading cause of liver dysfunction in non-alcoholic, and viral hepatitis negative
-Dallas Heart study –Szczepaniak et al. 2005 found 33.6% population have fatty liver,
only 5% of these experience complications from it
-Higher in Hispanics
-60-90% chance if obese, 50% is T2DM, 100% chance if T2DM and obese!
Genes affecting steatosis
Genes influencing hepatic free fatty acid and TG levels: PNPLA3 aka adiponutrin
-found in GWAS studies
-On chr 22, encodes a 461 aa protein related to the major hydrolase ATGL/PNPLA2
-An isoleucine Methionine substitution associated with increased severity of lipid
accumulation by promoting converting LPA phosphatidic acid
-I.e. = a ‘gain in function’ effect
-May sensitise liver to environmental stressors, increasing chance of hepatitis
Genes influencing hepatic free fatty acid and TG levels: Microsomal triglyceride transfer
protein
-G/T SNP at position 493 in 5’ promoter
-gives reduced MPT activity
-involved in VLDL synthesis, which causes failure of lipid export and more severe
steatosis (but not inflammation / NASH)
-loss of function causes abetalipoproteinaemia
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Hepatic steatosis = pathological definition of the presence of fat vesicles, predominantly triglycerides, accumulating within hepatocytes . Nafld = the presence of hepatic steatosis as part of the metabolic syndrome of obesity, insulin resistance / t2dmand dyslipidaemia . Nash = rare complication of nafld, where inflammation of the liver has occurred . Characteristic histological appearance in the absence of alcohol hx. Ballooning of fat droplets with chicken-wire fibrosis between hepatocytes. Causes of fatty liver can be primary or secondary: Secondary = alcohol, drugs (steroids, amiodorone, haart), hep c, parenteral nutrition. = leading cause of liver dysfunction in non-alcoholic, and viral hepatitis negative. 2005 found 33. 6% population have fatty liver, only 5% of these experience complications from it. 60-90% chance if obese, 50% is t2dm, 100% chance if t2dm and obese! Pathogenesis: steatosis 2) steatohepatitis 3) fibrosis 4)cirrhosis. Diet: high sat fat content, high fructose content. Obesity i. e. calorie intake>output, lack of exercise, increased portion size.
