Alterations in hepatic glucose and energy metabolism as a... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Alterations in hepatic glucose and energy metabolism as a result of calorie and carbohydrate restriction

Browning, Jeffrey D.1,2*; Weis, Brian4; Davis, Jeannie2; Satapati, Santhosh2; Merritt, Matthew2; Malloy, Craig R.1,2,5; Burgess, Shawn C.2,3

1_Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX_

2_The Advanced Imaging Research Center, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX_

3_Department of Pharmacology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX_

4_Department of Medicine, Texas Tech University Health Science Center School of Medicine at Amarillo, Amarillo, TX_

5_Veterans Affairs Medical Center, Dallas, TX_

* Address reprint requests to: Department of Internal Medicine, Division of Digestive and Liver Diseases and The Advanced Imaging Research Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8568

Email:[email protected]

Received 17 March 2008; Accepted 23 June 2008

Published online in Wiley InterScience (www.interscience.wiley.com).

Supported by National Institutes of Health (NIH); Grant Numbers: RL1DK081187 1K23DK074396-01 RR02584 DK078184.

Potential conflict of interest: Nothing to report.

fax: 214-645-2744.

Abstract

Carbohydrate restriction is a common weight-loss approach that modifies hepatic metabolism by increasing gluconeogenesis (GNG) and ketosis. Because little is known about the effect of carbohydrate restriction on the origin of gluconeogenic precursors (GNG from glycerol [GNGglycerol] and GNG from lactate/amino acids [GNGphosphoenolpyruvate {PEP}]) or its consequence to hepatic energy homeostasis, we studied these parameters in a group of overweight/obese subjects undergoing weight-loss via dietary restriction. We used 2H and 13C tracers and nuclear magnetic resonance spectroscopy to measure the sources of hepatic glucose and tricarboxylic acid (TCA) cycle flux in weight-stable subjects (n = 7) and subjects following carbohydrate restriction (n = 7) or calorie restriction (n = 7). The majority of hepatic glucose production in carbohydrate restricted subjects came from GNGPEP. The contribution of glycerol to GNG was similar in all groups despite evidence of increased fat oxidation in carbohydrate restricted subjects. A strong correlation between TCA cycle flux and GNGPEP was found, though the reliance on TCA cycle energy production for GNG was attenuated in subjects undergoing carbohydrate restriction. Together, these data imply that the TCA cycle is the energetic patron of GNG. However, the relationship between these two pathways is modified by carbohydrate restriction, suggesting an increased reliance of the hepatocyte on energy generated outside of the TCA cycle when GNGPEP is maximal. Conclusion: Carbohydrate restriction modifies hepatic GNG by increasing reliance on substrates like lactate or amino acids but not glycerol. This modification is associated with a reorganization of hepatic energy metabolism suggestive of enhanced hepatic β-oxidation. (Hepatology 2008;48:1487–1496.)

Abbreviations: BMI, body mass index; EGP, endogenous glucose production; GCRC, General Clinical Research Center; GNG, gluconeogenesis; MAG, monoacetone glucose; NAFLD, nonalcoholic fatty liver disease; NMR, nuclear magnetic resonance; PEP, phosphoenolpyruvate; PEPCK, phosphoenolpyruvate carboxykinase; RQ, respiratory quotient, TCA, tricarboxylic acid