310-OR: Role of Glucose Flux to Elevate Hepatic Lipogenesis in Biopsy-Proven NASH

Abstract

Hepatic de novo lipogenesis (DNL) contributes to the development of nonalcoholic fatty liver disease (NAFLD) and the more advanced form, nonalcoholic steatohepatitis (NASH). The purpose of the present study was to test the effects of glucose control on hepatic DNL in subjects with biopsy-proven NASH. Ten subjects [mean±SD, age 38.6±8.4y, BMI 42.2±5.9kg/m2, NAFLD activity score (NAS 1-8) of 5.7±1.3] completed metabolic studies to quantitate glucose oxidation (GluOx) measured by indirect calorimetry, liver fat by MRI/MRS, hepatic DNL using d2O administration, and VLDL-TG sources by GC/MS. Fed state GluOx was associated with NAS (Figure 1A) and fractional DNL (Figure 1B). Fasting GluOx was related to fibrosis (data not shown, r=0.690, P=0.027), ALT (r=0.631, P=0.051), AST (r=0.663, P=0.037), and absolute DNL (r=0.684, P=0.042). Subjects are participating in a 9-month diet/exercise intervention; six of whom have completed the trial increased VO2max (Figure 1C, P=0.015), reduced body mass 9.3±6.3% (P=0.008), DNL (P=0.045, n=5), liver fat (P=0.018), and ALT (P=0.001); NAS score fell from 6.3±1.0 to 3.8±2.2 (P=0.029). These data highlight how elevations in fasting and fed glycolysis can upregulate hepatic DNL to cause NASH. Lifestyle modifications that reduce DNL are likely to contribute to improvements in NAFLD/NASH. Disclosure J.M. Mucinski: None. N. Sharma: None. M.P. Moore: None. J.A. Ibdah: None. R. Rector: None. E.J. Parks: None. Funding National Institutes of Health (R01DK113701)