About

Marc Hellerstein is a Professor of Nutritional Sciences & Toxicology and holds the Robert C. and Veronica Atkins Chair in Metabolic Nutrition. He is associated with the Department of Nutritional Sciences & Toxicology at the University of California, Berkeley, and is part of the Center for Computational Biology. His role involves research and academic contributions in the fields of nutritional sciences, toxicology, and metabolic nutrition, with a focus on computational biology and related areas.

Research topics

• Gastroenterology
• Pathology
• Medicine
• Internal medicine
• Endocrinology

Selected publications

• Measurement of Glycolysis with Heavy Water Labeling

  Journal of Biological Chemistry · 2026-04-01

  articleOpen accessSenior author

  We introduce a method to calculate the contribution of glycolysis to lactate and the sources of cytosolic NADH, using heavy water labeling, mass spectrometric measurement and combinatorial analysis (mass isotopomer distribution analysis).The number (n) of deuterium incorporation sites into C-H bonds during flux through glycolysis versus the oxaloacetate/phosphoenolpyruvatecarboxykinase pathway is calculated.The stereospecificity of lactate dehydrogenase reveals the metabolic source of cytosolic NADH used because TCA cycle dehydrogenases have a different spatial orientation (reduce pyruvate from 4R position) than glycolytic glyceraldehyde-3-phosphate dehydrogenase (4S position, which derives intramolecularly, not from cellular H2O).We calculate n in lactate and validate the model in vivo in mouse liver and skeletal muscle and in HepG2 cells.We also compare lactate measurement of glycolysis from [U-13 C6]-glucose to M3-lactate.In summary, this heavy water method is operationally simple, provides information about both carbon fluxes and sources of NADH, and is translatable into humans.

  PublisherOA PDFDOI

• Nitric oxide required for transition to slower hepatic protein synthesis rates during long-term caloric restriction

  Journal of Clinical Investigation · 2026-01-01

  articleOpen accessSenior author

  Calorie restriction (CR) extends maximal lifespan and maintains cellular homeostasis in various animal models. We have previously shown that CR induces a global reduction of protein fractional synthesis rates (FSRs) across the hepatic proteome in mice, but the timing and regulatory mechanisms remain unclear. Nitric oxide (NO), a bioactive molecule upregulated during CR, is a potential regulator of protein synthesis. To explore the role of NO in hepatic proteome fluxes during CR, we used in vivo deuterium labeling from heavy water and liquid chromatography/mass spectrometry-based (LC/MS-based) flux proteomics in WT and NO-deficient (NO-) mice. We observed a transition to reduced global protein FSRs that occurred rapidly between days 25 and 30 of CR. NO deficiency, whether genetic or pharmacological, disrupted the slowing of proteome-wide fluxes and the beneficial effects on body composition and physiology. Administering the NO donor molsidomine restored the reduction in hepatic FSRs in NO- mice. Furthermore, inhibiting NO pharmacologically, whether starting on day 1, day 14, or day 24 of CR, mitigated the reduction in hepatic protein FSRs at day 32, highlighting NO's critical role during the transition period. These results underscore the importance of NO in CR-induced changes in proteostasis and suggest NO as a potential CR-mimetic target, while offering a specific time window for identifying other signals and testing therapeutic interventions.

  PublisherDOI

• Factors associated with protection from MASLD in type 2 diabetes: A prospective study integrating longitudinal MRI/MRE and stable isotope tracing

  JHEP Reports · 2026-01-08

  articleOpen access

  Background & Aims: Type 2 diabetes is one of the strongest risk factors for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we aimed to identify factors associated with protection from MASLD in a prospective cohort of individuals with type 2 diabetes. Methods: This prospective study included 148 individuals with type 2 diabetes who underwent advanced liver phenotyping using MRI and MRE techniques at baseline and 2-year follow-up. Protection from MASLD was defined as the absence of hepatic steatosis (MRI-proton density fat fraction <5%) and significant fibrosis (MRE <3 kPa) at both time points. Factors associated with protection from MASLD were assessed using Firth's penalized logistic regression. Regularized logistic regression models were fitted as complementary analyses. Results: lipogenesis in those free from MASLD. Conclusions: Managing modifiable risk factors, such as body weight and lipid profile, may be critical for preventing MASLD development in individuals with type 2 diabetes. Impact and implications: lipogenesis may underlie this protective phenotype. These findings suggest that managing modifiable risk factors, such as body weight and lipid profile, may be critical for preventing MASLD development and progression in individuals with type 2 diabetes.

  PublisherDOI

• 2154-LB: Rapid Appearance of Newly Synthesized Insulin and C-Peptide in Plasma (Reduced Residence Time in β-Cells) Is a Noninvasive Measure of Loss of Insulin Reserve in ZDF Rats

  Diabetes · 2025-06-13

  article1st authorCorresponding

  Introduction and Objective: T2D evolves through progressive loss of β-cell secretory capacity and insulin reserve. Non-invasive detection of insulin depletion in β-cells has not been possible. We tested a flux-based method for identifying reduced β-cell insulin stores non-invasively. The time for newly synthesized Ins and C-P to appear and become fully labeled in plasma reveals residence time (RT) in β-cells. We hypothesized that depleted insulin reserves results in new Ins and C-P passing through β-cells and appearing in plasma more rapidly (shorter RT). Methods: Female ZDF rats (n=24/group) were fed chow or high fat diet, the latter to induce T2D. 2H2 O was given for 1-48 hr, with high-resolution mass spectrometry of plasma Ins and C-P deuterium labeling patterns over time of 2H2 O exposure Results: Fractional synthesis rate (FSR) of Ins was significantly faster and RT (1.0/FSR) was shorter (A, RT 2.3 vs. 5.4 hr, p&amp;lt;0.0001) in T2D. RT of C-P also was shorter (B, 2.5 vs. 5.9 hr, p&amp;lt;0.0001) in T2D and correlated closely with Ins RT. plasma Ins or C-P RT measured at 3 or 6 hr differentiated all T2D from non-T2D rats (p&amp;lt;0.001). Other markers were consistent with β-cell failure. Conclusion: RT of Ins or C-P measured in plasma is a non-invasive window into depletion of β-cell insulin. This non-invasive assay of β-cell loss of secretory reserve is translatable into humans. Disclosure M.K. Hellerstein: Research Support; Lilly USA LLC. Consultant; Lilly USA LLC. E.J. Zanley: None. J. Willency: Employee; Eli Lilly and Company. V. Pirro: Employee; Eli Lilly and Company. O. Cabrera: Employee; Eli Lilly and Company. Funding Lilly LRAP

  PublisherDOI

• Supplementary Table 1 from Body Composition, Relative Dose Intensity, and Adverse Events among Patients with Colon Cancer

  2025-11-26

  articleOpen access

  &lt;p&gt;Supplementary Table 1. The Comparisons of Patient Characteristics in All (N = 178), CT (N = 170), DXA (N = 162), and D3Cr (N = 118) Groups&lt;/p&gt;

  PublisherDOI

• Metabolic labeling kinetics of brain-derived 24S-hydroxycholesterol in blood in multiple sclerosis: Effects of treatment with the remyelinating antibody rHIgM22

  Multiple Sclerosis Journal - Experimental Translational and Clinical · 2025-04-01 · 2 citations

  articleOpen accessSenior author

  Background: Cholesterol is an essential and major component of myelin. Brain cholesterol turnover in humans can be studied noninvasively by metabolic labeling of the brain-specific cholesterol metabolite, 24S-hydroxycholesterol (24-OHC), which is released into blood. Objectives: We examined the effects on brain cholesterol turnover in healthy individuals and in multiple sclerosis (MS) following treatment with placebo or the remyelinating monoclonal antibody, rHIgM22, which binds to oligodendrocytes and myelin. Methods: O) intake in age- and sex-matched non-MS and clinically stable relapsing-remitting MS subjects. Results: Incorporation and die-away of labeled 24-OHC revealed biphasic kinetics, with two kinetically distinct pools of brain cholesterol: a large, slow turnover pool and a smaller, metabolically more active pool of newly synthesized cholesterol. The latter showed significantly higher turnover rates in MS compared to non-MS subjects, which was significantly reduced in patients with MS treated with rHIgM22. Conclusions: Plasma 24-OHC kinetics provide a minimally invasive biomarker of brain cholesterol metabolism and revealed differences between healthy and clinically stable MS subjects, with increased turnover of the metabolically active 24-OHC pool that normalized in response to rHIgM22 therapy.

  PublisherDOI

• Myofibrillar Proteomics Of Sustained Load-carriage Hiking

  Medicine & Science in Sports & Exercise · 2025-09-16

  article
  PublisherDOI

• 2163-LB: Metabolic Fluxomics with Heavy Water Labeling

  Diabetes · 2025-06-13

  articleSenior author

  Introduction and Objective: We introduce a heavy water (2H2 O) labeling technique to measure fluxes across a metabolome. The principle is that metabolic pathways comprise enzymatic reactions that exchange hydrogen between solvent water and covalent C-H bonds. Methods: The number (n) of exchangeable C-H sites is calculated from combinatorial probabilities (isotope ratios) after 2H2 O labeling, in a single LC-MS/MS analysis. This reveals contributions from different pathways traversed. Results: We first validated targeted fluxes in vivo in mice - e.g., hepatic glycolysis and glyceroneogenesis; plasma gluconeogenesis. We then measured untargeted fluxomics in central metabolism (Figure), including effects of inborn errors (Citrin deficiency) and T2D. Global flux ratios include sources of UDP-glucose, glycolytic and TCA cycle intermediates, acetyl-CoA, pentose phosphates, amino acids, purines and pyrimidines. The list can be expanded. Fig. Central metabolic fluxes in mouse liver. Numbers represent n (exchangeable C-H bonds), revealing pathway contributions. Conclusion: Labeling with 2H2 O has several benefits over 13C- methods. 13C- tracers enter locally whereas 2H2 O is distributed globally, is immune to non-linear error propagation and label recycling, and experimental logistics are simpler. This method has implications for diabetes research. Metabolic flux signatures, changes during diabetogenesis and effects of therapeutics can be explored. This fluxomics technique is translatable to humans. Disclosure N. Ziari: None. M.K. Hellerstein: Research Support; Lilly USA LLC. Consultant; Lilly USA LLC. Funding University of California CRCC predoctoral fellowship

  PublisherDOI

• Supplementary Table 6 from Body Composition, Relative Dose Intensity, and Adverse Events among Patients with Colon Cancer

  2025-11-26

  articleOpen access

  &lt;p&gt;Supplementary Table 6. Sex-Specific Adjusted Associations of Body Composition Measurements (Per SD Increase) with Reduced RDI and Relative Changes (%) in the Number of Moderate and Severe Adverse Events&lt;/p&gt;

  PublisherDOI

• Supplementary Table 2 from Body Composition, Relative Dose Intensity, and Adverse Events among Patients with Colon Cancer

  2025-11-26

  articleOpen access

  &lt;p&gt;Supplementary Table 2. Sex-Specific Standard Deviations of Body Composition Measurements (CT SMA, DXA ALM, D3Cr Muscle, CT TAT, and DXA TBF)&lt;/p&gt;

  PublisherDOI

Recent grants

• NIH Grant R37AI043866

  NIH · $3.9M · 2013

• NIH Grant P01HD040543

  NIH · $12.0M · 2008

• NIH Grant R01AI043866

  NIH · $1.1M · 2002

• NIH Grant R21AI044767

  NIH · $451k · 2001

• NIH Grant R01DK040995

  NIH · $1.3M · 1997

Frequent coauthors

• Richard A. Neese

  University of California System

  144 shared

• Scott Turner

  Pliant (United States)

  140 shared

• Mahalakshmi Shankaran

  84 shared

• William J. Evans

  University of California, Berkeley

  82 shared

• Teresa W.‐M. Fan

  University of Kentucky

  64 shared

• Andrea E. Spencer

  64 shared

• Charles R. Owens

  The Medical Center of Aurora

  64 shared

• Courtney Pollard

  Piedmont Cancer Institute

  64 shared

Labs

• Center for Computational BiologyPI