Hepatic Steatosis Modulation by Apo B Gene Transcription

Summary

Principal Investigator: JANET DEHOFF SPARKS
Abstract: Over 50% of obese individuals with metabolic syndrome have increased hepatic triglycerides (TG) (steatosis) that predisposes them to non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) for which there is no consensus treatment. Human studies indicate that betaine, a naturally occurring micronutrient, alleviates hepatic steatosis, and reduces NASH, however, the mechanism responsible for this effect is not known. We have shown that dietary betaine in rats enhances hepatic apolipoprotein (apo) B synthesis through increased apob gene transcription which favors hepatic TG export in very low density lipoproteins (VLDL) and reduces liver TG content by 45%. This suggests a similar mechanism may be responsible for the reduction of hepatic steatosis observed in humans fed betaine. Aim 1 tests the ability of betaine to reverse hepatic steatosis in two rodent metabolic syndrome models: Zucker (fa/fa) rats and fructose-fed apobec-1-/- mice (B100). Zucker rats model overfeeding and fructose-fed mice model increased consumption of fructose. B100 mice serve as a model of human liver lipoprotein metabolism because B100 mice synthesize and secrete VLDL B100 rather than VLDL B48 and VLDL B100. In vivo VLDL production, hepatic lipid content, lipogenesis, bile acid synthesis, and -oxidation will be measured in rodents fed betaine. Aim 2 will define the transcription factors (TF) that mediate transactivation of the apob gene using gel shift assays, chromatin immunoprecipitation, and in vitro loss and gain of function studies in rodent hepatocytes. Aim 3 examines the role of DNA methylation in regulating apob gene expression as a potential mechanism of betaine action by assessment of global and promoter DNA hypomethylation and transient transfection assays using methylated promoter constructs. As increasing hepatic production of VLDL can lead to hypertriglyceridemia and increased LDL chol, betaine therapy will be tested in combination with reduced caloric intake. We suggest that induction of apob transcription may be beneficial in treating hepatic steatosis, and reducing the development of NASH and cirrhosis. What is favorable for the liver may not be favorable in the long term for cardiovascular risk, however, understanding the association gives us the ability to balance risk based on each organ's pathophysiology. Fatty liver disease is increasingly common in the obese human population, and can progress to liver disease including cirrhosis. Betaine may reverse fatty liver by favoring the unloading of hepatic fat into circulating lipoproteins. Clinical implications are direct as betaine is an available therapeutic micronutrient. Understanding the mechanism responsible for the action of betaine on apo B and serum lipoproteins could improve therapy by specific intervention by enhancing TG export from the liver. PUBLIC HEALTH RELEVANCE: Fatty liver disease is increasingly common in the obese human population, and can progress to liver disease including cirrhosis. Betaine may reverse fatty liver by favoring the unloading of hepatic fat into circulating lipoproteins. Clinical implications are direct as betaine is an available therapeutic micronutrient, and understanding the mechanism responsible for the action of betaine on apo B and serum lipoproteins could improve therapy by enhancing TG export from the liver.
Funding Period: ----------------2010 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Insulin suppression of apolipoprotein B in McArdle RH7777 cells involves increased sortilin 1 interaction and lysosomal targeting
    Jeffrey M Chamberlain
    Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Box 626, 601 Elmwood Avenue, Rochester, NY 14642, USA
    Biochem Biophys Res Commun 430:66-71. 2013
  2. pmc Metabolic regulation of APOBEC-1 complementation factor trafficking in mouse models of obesity and its positive correlation with the expression of ApoB protein in hepatocytes
    Chad A Galloway
    University of Rochester, Department of Biochemistry and Biophysics, 601 Elmwood Ave Rochester, NY 14642, USA
    Biochim Biophys Acta 1802:976-85. 2010
  3. pmc Interleukin-6 mediates hepatic hypersecretion of apolipoprotein B
    Janet D Sparks
    Dept of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, NY 14642, USA
    Am J Physiol Gastrointest Liver Physiol 299:G980-9. 2010
  4. pmc Acute suppression of apo B secretion by insulin occurs independently of MTP
    Janet D Sparks
    Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Box 626, 601 Elmwood Avenue, Rochester, NY 14642, USA
    Biochem Biophys Res Commun 406:252-6. 2011

Scientific Experts

  • JANET DEHOFF SPARKS
  • Jeffrey M Chamberlain
  • Chad A Galloway
  • Colleen O'Dell
  • Charles E Sparks
  • Harold C Smith
  • Robert A Mooney
  • John Ashton

Detail Information

Publications4

  1. pmc Insulin suppression of apolipoprotein B in McArdle RH7777 cells involves increased sortilin 1 interaction and lysosomal targeting
    Jeffrey M Chamberlain
    Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Box 626, 601 Elmwood Avenue, Rochester, NY 14642, USA
    Biochem Biophys Res Commun 430:66-71. 2013
    ..As BafA1 also prevents insulin suppressive effects on apo B secretion, our results suggest that sort1-B100 interaction stimulated by insulin transiently accumulates with BafA1 and favors B100 secretion by default...
  2. pmc Metabolic regulation of APOBEC-1 complementation factor trafficking in mouse models of obesity and its positive correlation with the expression of ApoB protein in hepatocytes
    Chad A Galloway
    University of Rochester, Department of Biochemistry and Biophysics, 601 Elmwood Ave Rochester, NY 14642, USA
    Biochim Biophys Acta 1802:976-85. 2010
    ....
  3. pmc Interleukin-6 mediates hepatic hypersecretion of apolipoprotein B
    Janet D Sparks
    Dept of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, NY 14642, USA
    Am J Physiol Gastrointest Liver Physiol 299:G980-9. 2010
    ..These changes may contribute to hypersecretion of VLDL associated with obesity, particularly under conditions where SOCS3 is not overexpressed to an extent capable of overcoming IL-6-stimulated apob gene transcription...
  4. pmc Acute suppression of apo B secretion by insulin occurs independently of MTP
    Janet D Sparks
    Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Box 626, 601 Elmwood Avenue, Rochester, NY 14642, USA
    Biochem Biophys Res Commun 406:252-6. 2011
    ..0±12.4% in control transfected hepatocytes. Results indicate that even under conditions of increased hepatic apo B secretion mediated by MTP, responsiveness of hepatocytes to insulin to suppress apo B secretion is maintained...