Poster Topical Area: Energy and Macronutrient Metabolism

Location: Hall D

Poster Board Number: 464

P10-064 - Biomarkers of Caloric Restriction (CR) Predict Non-Alcoholic Fatty Liver Disease (NAFLD) in the Multiethnic Cohort – Adiposity Phenotype Study (MEC-APS)

Monday, Jun 11
8:00 AM – 3:00 PM

Objectives:

CR is the most potent, robust, and reproducible known means of extending longevity and decreasing morbidity in lab rodents. Despite 80+ years of research, the relevance of this observation for humans remains unknown, but it is supported by the established link between obesity and morbidity in humans.

The MEC-APS investigated metabolites associated with NAFLD – the most common cause of chronic liver disease worldwide – across five major U.S. racial/ethnic groups, which vary in NAFLD frequency by a 2.5 fold. Although NAFLD is obesity-associated, prediction of NAFLD by total adiposity, including proxies such as weight and BMI, is not strong and differs across race/ethnic groups<./p>


Methods:


The MEC has followed 215,000 Hawaii and Los Angeles residents of African, Japanese, European, Latino, and Native Hawaiian ancestry since 1993-1996. In the MEC-APS, we measured liver fat using abdominal MRI and total body fatness by DXA in a cross-sectional subset of 1781 healthy women and men aged 60-77 years with BMIs of 17-46 kg/m2. Redox active plasma metabolites were assessed using HPLC separations with coulometric electrode array detection. Statistics: Mann-Whitney U, regression, AUROC.


Results:


Of 16 metabolites statistically associated with NAFLD, seven were previously linked to CR in studies of ad libitum fed and CR FBFN1 rats (males/females, different ages and extents and durations of CR). Strikingly, the strongest three NAFLD markers (p-7 in both sexes) were all previously CR-linked; all three are endogenous, very low concentration in plasma, structurally unidentified molecules that are followed using chromatographic and redox signatures. AUROCs for NAFLD (~0.75 in women/~0.85 in men) are comparable with the best available markers. AUROCs are essentially equal across liver fat cut-offs (4.0% to 6.5%) near the standard clinical threshold for NAFLD (>5.5%), suggesting robustness and the potential to recognize at-risk individuals. Limiting analysis to individuals who meet NAFLD alcohol consumption criteria strengthened the associations, suggesting that the markers capture the metabolic milieu specific to NAFLD, not overt fatty liver disease itself.


Conclusions:


Biomarkers of CR in rats predict NAFLD men and women from five ethnic groups in the MEC-APS.




Funding Source: P01 CA168530, U01 CA164973

CoAuthors: Marina Belenky – Brigham and Women's Hospital/Harvard Medical School; Defne Altan – Harvard College; Matthew Sniatynski – Brigham and Women's Hospital/Harvard Medical School; Vasant Marur – Brigham and Women's Hospital/Harvard Medical School; Rose Gathungu – Brigham and Women's Hospital/Harvard Medical School; Unhee Lim – 3University of Hawaii Cancer Center, University of Hawaii; Kris Monroe – 4Keck School of Medicine, University of Southern California; Thomas Ernst – John A Burns School of Medicine, University of Hawaii; John Shepherd – School of Medicine, University of California San Francisco; Steve Buchthal – John A Burns School of Medicine, University of Hawaii; Bo Fan – 6School of Medicine, University of California San Francisco; Iona Cheng – Cancer Prevention Institute of California; Meredith Hullar – Fred Hutchinson Cancer Research Center; Johanna Lampe – Fred Hutchinson Cancer Research Center; Timothy Randolph – Fred Hutchinson Cancer Research Center; Lynne Wilkens – University of Hawaii Cancer Center, University of Hawaii; Loic Le Marchand – University of Hawaii Cancer Center, University of Hawaii

Bruce Kristal

Associate Professor
Harvard Medical School/Brigham and Women's Hospital
Bosotn, Massachusetts