The Effect of Short Chain Fatty Acid Administration on Hepatic Glucose, Phosphate, Magnesium and Calcium Metabolism

Intra peritoneal administration of the short chain fatty acids, acetate, propionate and butyrate, in amounts calculated to reach 20 mM in total body water were given to fed and 48 hour starved male Wistar rats. One half hour after administration, the livers were freeze-clamped and the hepatic contents of various intermediary metabolites were measured. The liver content of total glycolytic intermediates was elevated by short chain fatty acids. In fed animals, the portion of glycolysis from fructose 1,6-bisphosphate (FBP) to PEP was elevated 2 to 4 fold. In 48 hour starved animals, where gluconeogenesis is active, the portion of the gluconeogenetic pathway from FBP to glucose was elevated 1.5 to 3.5 fold with the exception of the butyrate treated animals where blood glucose was not elevated. The metabolites of the hexose-monophosphate pathway that were measured, namely 6-phosphogluconate, ribulose 5-phosphate and xyulose 5-phosphate were increased in both fed and starved animals. The free cytoplasmic [NAD+] / [NADH],[NADP+] / [NADPH], and [ξATP] / [ξADP] X [ξPi) ratios were all decreased in both fed and starved animals after short chain fatty acid administration. The liver content of calcium increased 1.2 to 2 fold in fed animals and 2 to 3 fold in starved animals while total liver magnesium was either unchanged or increased only 1.2 times. The liver pyrophosphate (PPi) content increased a minimum of 10 fold in fed animals and over 100 fold in starved animals. In all cases no PPi could be detected in vivo by 31P NMR even though in the starved rats the PPi levels approached those of ATP. The liver content of inorganic Pi increased 1.3 to 1.5 fold in fed animals and 1.5 to 2 fold in starved animals. The total “rapidly metabolizing” Pi pool, that includes adenine and guanine nucleotides, glycolytic and shunt intermediates, Pi and PPi increased 1.3 times in fed animals (from 13.8 umole/g fresh weight) and 1.5 to 1.7 fold in starved animals (from 15.7 umol/g fresh weight). The total phosphate taken up from blood and entering the rapidly turning over pool of liver phosphate ranged between 4 and 12 umols/g of liver. It is concluded that the administration of short chain fatty acids whose activation produces inorganic PPi in the cytoplasm and/or the mitochondria have a profound effect on cellular metabolism by: (a) changing the distribution of energy between the various nucleotide pools such as the free cytoplasmic [NADP+] / [NADPH], [NAD+] / [NADH], and [ξATP] / [ξADP] × [ξPi] ratios, (b) elevating the steady state hepatic content of the metabolites of the hexosemonophosphate pathway and the glycolytic pathway, (c) altering the free cytoplasmic PPi and thus changing blood glucose concentrations according to the relation, $${{k}_{g}}=\frac{\left[ glucose-6-p \right]\ \left[ Pi \right]}{\left[ glu\operatorname{co}se \right]\ \left[ PPi \right]}=45.9,\ and$$ (d) increasing Pi, Ca and Mg transport into the liver.