Who studies metabolic regulation these days - the flow of metabolites through competing pathways in complex biological networks, the anabolic and catabolic processes that determine tissue composition, adaptations to environmental stresses and how their failure leads to disease? Not most Biochemistry or Molecular Biology departments. It is our belief that the study of physiologic chemistry (metabolic regulation) using modern tracer techniques and metabolic control concepts can be seized by nutrition researchers interested in making fundamental contributions to biochemistry and medicine (and in being funded).
Toward this end, our laboratory has focused on measuring a variety of intracellular metabolic processes not previously accessible to study in vivo. Our goal has always been to answer questions concerning the regulation of disease-modifying pathways by diet, genes, drugs and other factors, and to apply these techniques in humans. Because methods for studying the behavior of fully assembled, living systems have lagged remarkably – in comparison to techniques for characterizing chemical structure of isolated components of these systems, for example- much effort in our laboratory is spent on methods development. Accordingly, we have developed new in vivo stable isotope-mass spectrometric methods for measuring endogenous synthesis or transport rates of biomolecules such as fatty acids, cholesterol, proteins and carbohydrates and proliferation rates of cells. These techniques include mass isotopomer distribution analysis (MIDA), a universal technique for measuring polymerization biosynthesis; heavy water labeling for quantifying DNA replication and cell proliferation rates; dilution techniques for measuring reverse cholesterol transport fluxes; and methods for measuring the dynamics of brain molecules (among many others).
A number of basic questions in metabolic physiology have been addressed in this manner. Do humans convert excess carbohydrate calories to fat (surprisingly, no)? Do gene expression profiles accurately represent the flow of lipogenic and adipogenic pathways in adipose tissue of obese mice (no, pathway fluxes need to be measured)? Can the powerful effects of chronic caloric restriction on the promotional phase of carcinogenesis be replicated by alternate-day fasting regimens (yes, and even better, these regimens can be modified to permit some energy intake on the “fast” day, without loss of effects)? Can metabolic pathways in neurons in the brain be modulated and monitored for therapeutic benefit (very much so- the axonal microtubule assembly/disassembly cycle, for example, with effects on axonal transport of cargo; or new brain cell proliferation in the adult hippocampus). And so on.
Accordingly, our group is involved in a number of projects. These include studies of obesity/diabetes (the dynamics of adipose tissue components, including lipids, adipocytes, and macrophages) and dyslipidemias (reverse cholesterol transport and HDL functionality; sources of triglycerides secreted from the liver as VLDL); the effects of commonly used agents with important metabolic effects (cigarette smoking, alcohol); protein metabolism and body composition in wasting disorders (role of cytokines, rational development of new therapies including growth hormone, anabolic agents and anti-cytokines); specific nutrients (fructose, high carbohydrate diets, ethanol); and others.
Additional Information is available at the Hellerstein Lab page: www.hellersteinlab.berkeley.edu
Most Recent Publications
Akondy RA, Fitch M, Edupuganti S, Yang S, Kissick HT, Li KW, Youngblood BA, Abdelsamed HA, McGuire DJ, Cohen KW, Alexe G, Nagar S, McCausland MM, Gupta S, Tata P, Haining NW, McElrath MJ, Zhang D, Hu B, Greenleaf WJ, Goronzy JJ, Mulligan MJ, Hellerstein M# and Ahmed R# (# corresponding authors). Tracking the origin and differentiation of human memory CD8 T cells after vaccination. Nature (In press), 2017.
Decaris ML, Li KW, Emson CL, Gatmaitan M, Liu S, Wang Y, Nyangau E, Colangelo M, Angel TE, Beysen C, Cui J, Hernandez C, Lazaro L, Brenner DA, Turner SM, Hellerstein MK, Loomba R. Identifying nonalcoholic fatty liver disease patients with active fibrosis by measuring extracellular matrix remodeling rates in tissue and blood. Hepatology. 2017;65(1):78-88. PMID: 27706836
Shankaran M, King CL, Angel TE, Holmes WE, Li KW, Colangelo M, Price JC, Turner SM, Bell C, Hamilton KL, Miller BF, Hellerstein MK. Circulating protein synthesis rates reveal skeletal muscle proteome dynamics. J Clin Invest. 2016; 126(1):288-302. PMID: 26657858
Holmes W., Angel T., Li K., & Hellerstein MK. Dynamic Proteomics: In vivo proteome-wide measurement of protein kinetics using metabolic labeling. Methods Enz. 2015; 561:219-76. PMID: 263589072015
Clark RV, Walker AC, O'Connor-Semmes RL, Leonard MS, Miller RR, Stimpson SA, Turner SM, Ravussin E, Cefalu WT, Hellerstein MK, Evans WJ. Total body skeletal muscle mass: estimation by creatine (methyl-d3) dilution in humans.J Appl Physiol (1985). 2014; 116(12):1605-13. PMID: 24764133
Hellerstein MK. A critique of the molecular target-based drug discovery paradigm based on principles of metabolic control: advantages of pathway-based discovery. Metab Eng 10:1-9, 2008. PMID: 17962055
Busch R, Neese RA, Awada M, Hayes GM, Hellerstein MK. Measurement of cell proliferation by heavy water labeling. Nat Protoc 2:3045-57, 2007. PMID: 18079703
Busch R, Kim YK, Neese RA, Schade-Serin V, Collins M, Awada M, Gardner JL, Beysen C, Marino ME, Misell LM, Hellerstein MK. Measurement of protein turnover rates by heavy water labeling of nonessential amino acids. Biochim Biophys Acta 1760:730-44, 2006. PMID: 16567052
Macallan DC, Fullerton CA, Neese RA, Haddock K, Parks S, Hellerstein MK. Measurement of cell proliferation by labeling of deoxyribonucleic acid with stable isotope-labeled glucose: studies in vitro, in animals and in humans. Proc Natl Acad Sci USA:95:708-13, 1998. PMID: 9435257
Hellerstein MK, Neese RA. Mass isotopomer distribution analysis at eight years: theoretical, analytic and experimental considerations. Am J Physiol 276:E1146-70, 1999. PMID: 10362629