In addition to the regulation of metabolism by gene expression, mechanisms exist that allow pathways to respond to acute metabolic conditions. Common metabolic mechanisms that contribute to metabolic regulation are substrate supply, redox state, and cofactor availability.
These mechanisms are especially important for complex pathways that traverse multiple metabolic systems or cellular compartments and depend on substrate supply by other tissue. Hepatic gluconeogenesis uses metabolic regulation to coordinate glucose synthesis with substrate supply from peripheral tissues and energy production in the hepatocyte.
Most gluconeogenic substrates must be transported into mitochondria, undergo anaplerosis into the tricarboxylic acid cycle, and then be transported out of the mitochondria before being converted to glucose. The process is energetically expensive and, thus, requires ancillary coordination with energy production through fat oxidation, TCA cycle metabolism, and respiration.
The state of these supporting pathways effect metabolic factors that influence gluconeogenic flux.
We are studying how pathways of substrate delivery, transport, anaplerosis, cataplerosis, and energy metabolism act in conjunction with molecular mechanisms to regulate gluconeogenesis and other biosynthetic pathways that are abnormal during disease.
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