Katherine Kern

NTR401 Article Summary

November 11, 2016
The article Effect of a High-Fructose Weight-Maintaining Diet on Lipogenesis and Liver
Fat was published in the Journal of Clinical Endocrinology and Metabolism in June 2015. The
authors of the article are Jean-Marc Schwarz, Susan M. Noworolski, Michael J. Wen, Artem
Dyachenko, Jessica L. Prior, Melissa E. Weinberg, Laurie A. Herraiz, Viva W. Tai, Nathalie
Bergeron, Thomas P. Bersot, Madhu N. Rao, Morris Schambelan, and Kathleen Sullivan. The
purpose of the study was to evaluate the effect of a high-fructose, weight-maintaining diet on
fatty acid synthesis in the liver compared to a weight-maintaining diet in which complex
carbohydrate was substituted for fructose.
The study included 8 healthy men aged 18-65 years with a body mass index (BMI) less
than 30. Exclusion criteria included liver disease, hepatitis, diabetes, and HIV infection. During
the study, the 8 participants were hospitalized for 18 days. Each participant was fed a diet high in
fructose (20-25% of energy intake) for 9 days, and a diet that substituted complex carbohydrates
for fructose for 9 days. Both diets had the same macronutrient distribution of 15% protein, 35%
fat, and 50% carbohydrate. 4 of the participants were fed the high-fructose diet first, while the
other 4 were fed the complex carbohydrate diet first. Body fat and lean body mass were
measured at baseline and the end of each dietary period by dual-energy x-ray absorptiometry.
Energy expenditure and substrate oxidation rates were measured via indirect calorimetry, and
liver fat was measured via magnetic resonance spectroscopy. Stable isotope tracer solutions were
used to measure lipogenesis during both fasting and feeding.
As a result of the study, both body weight and body fat percentage remained the same for
all participants. Results of indirect calorimetry showed lipid oxidation was significantly lower
after the high-fructose diet than after the complex carbohydrate diet for all participants. Rate of
lipogenesis during fasting was not significantly different between the two diets, however during
feeding lipogenesis was significantly higher in the high-fructose diet. Liver fat was greater in all
participants after being fed the high-fructose diet. The order in which the diets were fed did not
affect the results of the study. The key finding of the study was that consumption of a high-

fructose diet stimulates lipogenesis when energy balance is neutral and both weight and body fat
are maintained.
A key metabolic pathway that is important in this study is the conversion of sugar to fat
in the liver, otherwise known as lipogenesis. After fructose is absorbed in the intestine, it is
rapidly taken up by the liver. The enzyme fructokinase is present in the liver, which
phosphorylates fructose to fructose-1-phosphate. Fructose-1-phosphate can then be converted to
dihydroxyacetone phosphate and glyceraldehyde and enter the glycolytic pathway. The
glycolytic pathway yields pyruvate, which is converted to acetyl-CoA via the pyruvate
dehydrogenase complex. In the fed state, acetyl-CoA is converted into fatty acids during fatty
acid synthesis. During this process, malonyl-CoA is added to acetyl-CoA via a complex of
enzymes known as the fatty acid synthase complex. The series of reactions involved in fatty acid
synthesis include condensation, reduction with NADPH, dehydration, and reduction with
NADPH. The result of this is synthesis of a 16-carbon fatty acid known as palmitic acid. The
fatty acids that are synthesized are then added to glycerol to form triglycerides. Triglycerides are
exported from the liver on very low-density lipoproteins (VLDLs) to peripheral tissues and
stored in adipose tissue. As the rate of lipogenesis increases in the liver, as it does during periods
of excessive simple carbohydrate intake, not all of the triglycerides are exported to peripheral
tissues. The triglycerides that are not exported are retained in the liver, which can result in fatty
liver.
In order to understand the effects of lipogenesis in the liver on substrate utilization, the
effects of lipogenesis on the regulation of fatty acid oxidation (beta-oxidation) must be
examined. During lipogenesis, acetyl-CoA must be converted to malonyl-CoA. When rates of
lipogenesis increase, the concentration of malonyl-CoA also increases in the cell. Malonyl-CoA
is a substance that inhibits the enzyme carnitine acyltransferase I, which has the effect of
inhibiting the beta-oxidation pathway. Carnitine acyltransferase I is involved in the transport of
fatty acyl-CoA into the mitochondria for beta-oxidation. When this enzyme is inhibited, the
transport does not occur and thus newly formed fatty acids are not transported into the
mitochondria for oxidation. The inhibition of beta-oxidation changes the ratio of substrate
utilization, as demonstrated in the results of the study showing decreased lipid utilization.

Understanding the metabolic pathway of lipogenesis was integral for understanding the
results of this study. In addition, understanding the regulatory mechanisms of the beta-oxidation
pathway and how intermediaries in lipogenesis inhibit beta-oxidation is also essential.

Reference
Schwarz, J.-M., Noworolski, S. M., Wen, M. J., Dyachenko, A., Prior, J. L., Weinberg, M. E.,
Mulligan, K. (2015). Effect of a High-Fructose Weight-Maintaining Diet on Lipogenesis
and Liver Fat. The Journal of Clinical Endocrinology and Metabolism, 100(6), 2434
2442. http://doi.org/10.1210/jc.2014-3678