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CHAPTER 14 Food, through metabolism, provides the nutrients necessary for homeosta-

METABOLISM OF sis, repair, and reproduction of many organisms. To align supply and demand,
mammalian metabolism is linked to sleep cycles through the central circadian
HEMATOLOGIC NEOPLASTIC clock that senses light and dark phases of the day via the eye and central ner-
vous system. The central regulation of feeding and sleeping cycles coordinates
CELLS nutrient availability from food with the circadian oscillation of metabolism of
individual cells, which all have a molecular clock comprised of a network of
transcription factors that regulates cell metabolism.
2
Food is digested, absorbed through the gastrointestinal tract, and in part
3
Zandra E. Walton, Annie L. Hsieh, and Chi V. Dang processed or stored in the liver, which is a key metabolic organ. Processed
lipids in the form of lipoproteins are synthesized in the liver and dissemi-
nated throughout to supply the needs of various organs. Amino acids, with
SUMMARY glutamine circulating at the highest level (0.5 mM), supply cells with build-
ing blocks for proteins. Some amino acids (nonessential) are synthesized by
The quantum physicist Erwin Schrodinger surmised in his monograph “What humans, but essential amino acids must be available from the diet. Complex
is Life?” that the organized matter known as life needs to feed on “negative carbohydrates are broken down and circulate as glucose, a vital nutrient for
entropy” to avoid decay. He concluded that this feeding on negative entropy virtually all mammalian cells. In this regard, an endocrine system (insulin and
1
is achieved through metabolism, a term derived from Greek that describes glucagon) has evolved to control the circulating levels of this precious bioen-
an exchange of materials. Because of this centrality to life, metabolism’s core ergetic molecule. When in excess, amino acids and sugars contribute to lipo-
pathways—glycolysis and respiration—evolved early in Earth’s history and genesis, and the extra energy is stored as fat depots in adipose tissues. Excess
are highly conserved. At every stage of life, metabolism provides the needed glucose is stored as glycogen, which is deployed to release glucose in starved
nutrients, energy, and building blocks. Embryogenesis, for instance, requires conditions. It is believed that, during our evolution, periods of gorging and
metabolism of maternally derived nutrients to support cellular repair, growth, feeding were separated by significant durations of starvation; hence, we have
division, and differentiation. In particular, cell replication requires that the evolved mechanisms to survive starvation.
instructions emanating from the DNA sequence, modulated by the epige- In contrast to the fed state, when insulin level increases in response to
nome, couple with the import of nutrients and metabolic pathways to produce rising glucose to trigger cellular glucose uptake and storage, the starved
the components and energy necessary to build two copies of a cell and main- state triggers glucagon secretion from the pancreas, which mobilizes cellular
tain high replication fidelity of the genome. During growth and development, glycogen stores as nutrient. Prolonged starvation depletes liver and muscle
and especially during adulthood, metabolism also plays the important role of glycogen stores—the only major glycogen stores—and prompts the mobi-
providing bioenergetics for cellular and organismal homeostasis. Metabolism lization of fat stores. The released fatty acids provide glycerol as a substrate
can also feature prominently in disease, and this chapter discusses how the for making glucose through gluconeogenic pathways and fatty acids for mito-
metabolic pathways central to life and normal biology can be subverted in chondrial oxidation. Further prolonged starvation triggers the liver to convert
cancer to fuel abnormal growth. fatty acids to ketone bodies, which can cross the blood–brain barrier to feed

Acronyms and Abbreviations: ABC, activated B-cell type; ALL, acute lymphoid leuke- that upregulates glycolysis (known as MLXIP, MLX interacting protein); mTOR, mamma-
mia; AML, acute myeloid leukemia; AMPK, adenosine monophosphate kinase; ASCT2, ASC lian target of rapamycin; mTORC1, mTOR complex 1; MYC, a protooncogene that is a major
amino-acid transporter 2; ATRA, all-trans retinoic acid; BPTES, a glutaminase inhibitor; CDK, regulator of cell growth and metabolism; NADH, nicotinamide adenine dinucleotide;
cyclin-dependent kinase; CL, cardiolipin; COO, cell of origin; DFMO, α-difluoromethylorni- NADPH, nicotinamide adenine dinucleotide phosphate; NAMPT, nicotinamide phos-
thine; DLBCL, diffuse large B-cell lymphoma; eIF5A, eukaryotic translation initiation factor; phoribosyltransferase; NRF2, nuclear respiratory factor-2; NTP, nucleotide triphosphate;
ERK, extracellular regulated kinase; ETC, mitochondrial electron transport chain; Ets, E26, E ODC, ornithine decarboxylase; OGDH, oxoglutarate dehydrogenase; OXPHOS, oxidative
twenty-six; F1,6BP, fructose 1,6 biphosphate; F2,6BP, fructose 2,6 biphosphate; FAO, fatty phosphorylation; 53, activates oxidative phosphorylation and inhibits glycolysis; PC,
P
acid oxidation; FDG-PET, fluorodeoxyglucose positron emission tomography; FH, fumarate phosphatidyl choline; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase
hydratase; FOS, a protooncogene; G3P, glycerol 3-phosphate; G6PD, glucose-6-phosphate kinase; PE, phosphatidyl ethanolamine; PEP, phosphoenol pyruvate; PFK, phosphofruc-
dehydrogenase; GAP, glyceraldehyde 3-phosphate; GCB, germinal center B-cell type; tokinase; PG, glycerophosphoglycerol; PGC1α, an activator of mitochondrial biogenesis;
GDP, guanosine-5′-diphosphate; GLS, glutaminase; GLUT, glucose transporter; GM-CSF, PI, phosphatidyl inositol; PI3K, phosphoinositol 3′-kinase; PML, promyelocytic leukemia;
granulocyte-macrophage colony-stimulating factor; GOT, glutamate oxaloacetate tran- PRPS, 5-phosphoribosyl-pyrophosphate synthetase; PS, phosphatidyl serine; PTEN, phos-
saminase; GPI, glucose phosphate isomerase; GPT, glutamate pyruvate transaminase; phatase and tensin homologue deleted on chromosome 10, an antioncogene; RAS, name
GTP, guanosine-5’-triphosphate; 2-HG, 2-hydroxyglutarate; HIF, hypoxia-inducible factor; given to a family of related proteins belonging to small GTPase involved in signal trans-
HSC, hematopoietic stem cell; IDH, isocitrate dehydrogenase; IMPDH, inosine monophos- duction; ROS, reactive oxygen species; rRNA, ribosomal RNA; SAM, S-adenosylmethion-
phate dehydrogenase; LDHA, lactate dehydrogenase A; LKB1, Liver kinase B1; LSC, leuke- ine; SCO , cytochrome c oxidase; SDH, succinate dehydrogenase; SLC1A5, ASC amino-acid
2
mic stem cell; Max, Myc-associated factor X; MDM2, mouse double minute 2 homolog; transporter 2; SOD, superoxide dismutase; TCA, tricarboxylic acid; TET, family of dioxyge-
Miz-1, Myc-interacting zinc finger protein 1; MLL2, mixed-lineage leukemia protein 2; nases that catalyze conversion of 5-methylcytosine to 5-hydroxymethylcytosine; TFEB,
Mlx, Max-like protein X; MondoA, member of the MYC network of transcription factors transcription factor EB; THF, tetrahydrofolate; VHL, von Hippel-Lindau protein.

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