Carbohydrate Restriction Improves Fatty Liver

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.)

Since the seminal observation of Keys1 in 1980, the recommended diet in the United States has been the low-calorie, low-fat diet. This diet originated primarily as an inexpensive approach to prevent cardiovascular disease but has now become the recommended treatment for overweight and obesity in clinical practice.2 Despite the success of clinicians and the U.S. Public Health Service in reducing the U.S. population's fat intake and increasing its carbohydrate intake over the past 30 years, the prevalence of obesity has continued to rise.3, 4 During this same period, metabolic liver disease has become increasingly prevalent, taking the form of excess triglyceride accumulation in the liver that can result in inflammation, fibrosis, and cirrhosis.5, 6 The transition of this type of liver disease, known as nonalcoholic fatty liver disease (NAFLD), from relatively bland, inactive steatosis to a more morbid inflammatory condition, termed nonalcoholic steatohepatitis, occurs in a subset of individuals. The reason this transition takes place is unclear; however, some investigators have found a strong association between dietary carbohydrate intake and severity of both steatosis and steatohepatitis.7, 8 Current evidence suggests that a high carbohydrate diet leads to increased hepatic de novo lipogenesis,9 likely as the result of the molecular mediators carbohydrate and sterol response element binding protein.5 Such an increase in hepatic fat synthesis would be anticipated to be associated with hepatic steatosis; however, the connection between carbohydrate intake and inflammatory activity remains elusive. The changes in hepatic metabolism and energy production that occur as a consequence of changes in dietary carbohydrate intake may be important in the pathogenesis and progression of NAFLD.

Several studies have used stable isotopes to investigate the impact of carbohydrate intake on hepatic glucose metabolism.10–12 These studies clearly show that low-carbohydrate diets result in a reorganization of hepatic glucose production by changing the rate of glycogenolysis and, to a lesser degree, the rate of gluconeogenesis (GNG). However, little is known about the effect of carbohydrate restriction on the origin of gluconeogenic precursors (GNG from lactate/amino acids or glycerol) or its consequence on hepatic energy homeostasis. There is an empirical relationship between GNG and tricarboxylic acid (TCA) cycle flux13: suppressed rates of GNG result in impaired hepatic TCA cycle flux,14, 15 while increased GNG is accompanied by elevated TCA cycle flux.16 This relationship appears to be an “energetic rheostat,” allowing the liver to match energy production with the requirements of GNG. If the increased rates of GNG observed during carbohydrate restriction are the result of increased conversion of lactate/amino acids to glucose, energy production at the level of the TCA cycle may be altered in a coordinated manner.

To gain a better understanding of hepatic energy production and its relationship to GNG under conditions of varied macronutrient intake, we used 2H and 13C tracers combined with nuclear magnetic resonance (NMR) spectroscopy17 to simultaneously assess endogenous glucose production (EGP), glycogenolysis, GNG from lactate/amino acids (GNGphosphoenolpyruvate [PEP]), GNG from glycerol (GNGglycerol) pyruvate cycling, and TCA cycle flux in human subjects following a carbohydrate restricted or calorie restricted diet.