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Clinical Trial
. 2021 Dec 15;131(24):e150996.
doi: 10.1172/JCI150996.

Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease

Catherine C Cohen  1   2 , Kelvin W Li  3 , Adina L Alazraki  4   5 , Carine Beysen  6 , Carissa A Carrier  7 , Rebecca L Cleeton  1 , Mohamad Dandan  3 , Janet Figueroa  1 , Jack Knight-Scott  5 , Cynthia J Knott  8 , Kimberly P Newton  7   9 , Edna M Nyangau  3 , Claude B Sirlin  10 , Patricia A Ugalde-Nicalo  7   9 , Jean A Welsh  1   11 , Marc K Hellerstein  3 , Jeffrey B Schwimmer  7   9 , Miriam B Vos  1   11
Affiliations
Clinical Trial

Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease

Catherine C Cohen et al. J Clin Invest. .

Abstract

BACKGROUNDHepatic de novo lipogenesis (DNL) is elevated in nonalcoholic fatty liver disease (NAFLD). Improvements in hepatic fat by dietary sugar reduction may be mediated by reduced DNL, but data are limited, especially in children. We examined the effects of 8 weeks of dietary sugar restriction on hepatic DNL in adolescents with NAFLD and correlations between DNL and other metabolic outcomes.METHODSAdolescent boys with NAFLD (n = 29) participated in an 8-week, randomized controlled trial comparing a diet low in free sugars versus their usual diet. Hepatic DNL was measured as percentage contribution to plasma triglyceride palmitate using a 7-day metabolic labeling protocol with heavy water. Hepatic fat was measured by magnetic resonance imaging-proton density fat fraction.RESULTSHepatic DNL was significantly decreased in the treatment group (from 34.6% to 24.1%) versus the control group (33.9% to 34.6%) (adjusted week 8 mean difference: -10.6% [95% CI: -19.1%, -2.0%]), which was paralleled by greater decreases in hepatic fat (25.5% to 17.9% vs. 19.5% to 18.8%) and fasting insulin (44.3 to 34.7 vs. 35.5 to 37.0 μIU/mL). Percentage change in DNL during the intervention correlated significantly with changes in free-sugar intake (r = 0.48, P = 0.011), insulin (r = 0.40, P = 0.047), and alanine aminotransferase (ALT) (r = 0.39, P = 0.049), but not hepatic fat (r = 0.13, P = 0.532).CONCLUSIONOur results suggest that dietary sugar restriction reduces hepatic DNL and fasting insulin, in addition to reductions in hepatic fat and ALT, among adolescents with NAFLD. These results are consistent with the hypothesis that hepatic DNL is a critical metabolic abnormality linking dietary sugar and NAFLD.TRIAL REGISTRYClinicalTrials.gov NCT02513121.FUNDINGThe Nutrition Science Initiative (made possible by gifts from the Laura and John Arnold Foundation, Ambrose Monell Foundation, and individual donors), the UCSD Altman Clinical and Translational Research Institute, the NIH, Children's Healthcare of Atlanta and Emory University's Children's Clinical and Translational Discovery Core, Children's Healthcare of Atlanta and Emory University Pediatric Biostatistical Core, the Georgia Clinical and Translational Science Alliance, and the NIH National Institute of Diabetes, Digestive, and Kidney Disease.

Keywords: Carbohydrate metabolism; Hepatology; Insulin; Metabolism; Obesity.

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Conflict of interest statement

Conflict of interest: JBS has received research support from Galmed, Intercept, Genfit, and Seraphina. CBS has served as a consultant representative of the University of California Regents for GE Healthcare, Bayer, Boehringer Ingelheim, AMRA, Fulcrum Therapeutics, Medscape, and Resoundant; has served on scientific advisory boards for AMRA, Guerbet, and VitualScopics; is receiving research grants from ACR Innovation, Bayer, Gilead, GE Healthcare, General Electric, Philips, and Siemens; has served as a consultant for AMRA, Boehringer Ingelheim, Epigenomics, and Guerbet; has served on the speaker’s bureau for Resoundant and General Electric; has laboratory service agreements with Enanta, Genzyme, Gilead, Icon Medical Imaging, Intercept, Janssen, NuSirt, Shire, Synageva, Takeda, and VitualScopics; has received royalties from Wolters Kluwer for educational materials; serves on the advisory board for Quantix Bio; and owns stock options in Livivos. MBV has received grant support from Resonance Health, Immuron, Gemphire, Shire, and Target Pharmasolutions; and personal fees from AMRA, Immuron, Intercept, Target Pharmasolutions, Shire, Bristol-Myers Squibb, Boehringer Ingelheim, and Axcella Health.

Figures

Figure 1
Figure 1. Flow diagram of participants included in the present analysis.
This figure was adapted from the flow diagram for the original intervention trial by Schwimmer et al. (23) and expanded on. ABased on alanine aminotransferase level, the magnetic resonance imaging–proton density fat fraction percentage, or diagnosis of diabetes at baseline. Abbreviations: MRI, magnetic resonance imaging. DNL, de novo lipogenesis.
Figure 2
Figure 2. Clinical trial design and procedures.
Depicted is the timing of the DNL stable isotope tracer protocol (50 mL of 2H2O two times a day for 7 days), fasting blood draws, dried blood spot collection, and magnetic resonance imaging (MRI) throughout the duration of the intervention. All dried blood spots were collected at the same time as the fasting blood draw, except on day 47 (start of the second labeling period) when only a dried blood spot was collected to correct for the residual isotopic enrichment from the baseline labeling period. The purpose of the dried blood spot was to limit the number of blood draws.
Figure 3
Figure 3. Individual changes in de novo lipogenesis (DNL) in adolescent boys with NAFLD from baseline to week 8 by treatment group.
In the control group (n = 13), participants consumed their usual diet for 8 weeks. In the treatment group (n = 16), participants were provided a diet that was low in free sugars for 8 weeks. In the control group, 2 participants did not complete the hepatic DNL protocol at week 8, but their baseline hepatic DNL is still included in this figure.
Figure 4
Figure 4. Scatter plots showing correlations between percentage change in hepatic DNL and free-sugar intake, hepatic fat (MRI-PDFF), fasting insulin, and ALT after the 8-week interventions.
(A) Full sample. (B) Treatment group. Correlation coefficients and P values were calculated based on Pearson’s correlations. Trend lines and 95% confidence intervals were calculated by linear regression (method = “lm” in the ggplot2 package of R). In the control group, 2 participants were missing DNL data at week 8 and 1 participant had an outlier value for percentage change DNL (+480%) and were excluded from all plots. In the treatment group, 1 participant was missing hepatic fat (MRI-PDFF) data at week 8 and 1 participant was missing insulin data at week 0 and both were excluded from specific plots. MRI-PDFF, magnetic resonance imaging–proton density fat fraction; ALT, alanine aminotransferase.
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