Show notes:

A Non-invasive Method to Assess Hepatic Acetyl-CoA In Vivo (Perry and Shulman et al. 2017)

Background

• Futile fat cycling “Regulation is easier if competing reactions are maintained in a cycling steady-state and then biased in one or another direction. This becomes, in the end, more efficient  than starts and stops in response to different conditions”
• Acetyl-CoA contributes to GNG, glucose oxidation, protein acetylation and the synthesis of steroids as well as fatty acids
• Episode 1 Break Nutrition study reviewed ⇒ “reduction in hepatic acetyl-CoA content is a key mediator of insulin’s ability to acutely suppress hepatic gluconeogenesis in vivo”
• The hepatic acetyl-CoA content in the liver of rats subjected to the following 5 experimental conditions ranges from 40 to 250 nmol/g
  • Chow-fed rats
  • HFD-fed rats
  • poorly controlled T1D rats
  • poorly controlled T2D rats
  • hyperinsulinemic-euglycemic clamped rats
  • safflower-oil-based HFD  (59% fat, 26% carbs, 15% protein) for 4 weeks

Methods

• In vivo
• Used ketone salt ?-OHB
• DIDN’T look at acetoacetate
• measures performed after a 16-hr overnight fast ⇒ almost totally depletes hepatic glycogen content ⇒ here, rates of hepatic glucose almost entirely reflect rates of hepatic gluconeogenesis
  • other measures after a 6-hr fast (hepatic glycogen repleted) vs 48hr-fast (hepatic glycogen depleted) group

Results

“rates of ?-OHB turnover correlate very strongly with hepatic acetyl-CoA content in vivo (R2 = 0.86, p < 0.0001) across a 5-fold range of acetyl-CoA concentrations in five rat models with varying degrees of fasting hyperglycemia and insulin resistance”

• 4.5-fold difference in total endogenous glucose production (1 to 6 µmol/min)
• 3.5-fold difference in hepatic acetyl-CoA
• R2 = 0.95, p = 0.005 ⇒ ?-OHB turnover rates and hepatic acetyl-CoA concentrations in the five groups studied
• R2 = 0.79, p < 0.0001⇒ between rates of HGP and hepatic acetyl-CoA content
• Hans Krebs et al. “failed to observe a relationship between blood ketone concentrations and hepatic acetyl-CoA content” ⇒ another textbook claim falls…
• Glycerol at 60 µmol/(kg/min) ⇒ 3-fold increase plasma glycerol ⇒ increased HGP ⇒ compensatory rise in insulin
• “mirror the findings of Rawat and Menahan, who showed that intramuscular injection of gluconeogenic substrates (fructose, glyceraldehyde, and sorbitol) raised blood glucose concentrations and suppressed both hepatic acetyl-CoA content and blood ketone concentrations”
• “in the physiologically relevant comparison between starved and recently fed animals, rates of whole-body glucose production do not track with hepatic acetyl-CoA content”
  • What tracks better in both starved/recently fed states is rates of ?-OHB turnover
• “whole-body glucose production cannot be used as a reliable surrogate for hepatic acetyl-CoA content”
  • “rates of whole-body glucose turnover correlate with hepatic acetyl CoA content only when glucose turnover is mostly derived from pyruvate carboxylase flux”

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