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. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK078131-01A1
Application #
7462838
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Doo, Edward
Project Start
2008-04-01
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
1
Fiscal Year
2008
Total Cost
$261,800
Indirect Cost
Name
University of Rochester
Department
Pathology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Chamberlain, Jeffrey M; O'Dell, Colleen; Sparks, Charles E et al. (2013) Insulin suppression of apolipoprotein B in McArdle RH7777 cells involves increased sortilin 1 interaction and lysosomal targeting. Biochem Biophys Res Commun 430:66-71
Sparks, Janet D; Chamberlain, Jeffrey M; O'Dell, Colleen et al. (2011) Acute suppression of apo B secretion by insulin occurs independently of MTP. Biochem Biophys Res Commun 406:252-6
Sparks, Janet D; Cianci, Joanne; Jokinen, Jenny et al. (2010) Interleukin-6 mediates hepatic hypersecretion of apolipoprotein B. Am J Physiol Gastrointest Liver Physiol 299:G980-9
Galloway, Chad A; Ashton, John; Sparks, Janet D et al. (2010) 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. Biochim Biophys Acta 1802:976-85
Sparks, Janet D; Dong, Henry H (2009) FoxO1 and hepatic lipid metabolism. Curr Opin Lipidol 20:217-226