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Nonproliferating Versus Proliferating Cells

A Comparison of Metabolic Needs in Nonproliferating and Proliferating Cells

Although most of this chapter deals with the extraction of energy from glucose through the production of ATP in glycolysis (anaerobic) and the TCA cycle and oxidative phosphorylation (aerobic) in the mitochondria, cells have other needs that must be met, especially  the need for reductive biosynthesis to produce fatty acids, proteins, and nucleic acids. Which need prevails? Vander Heiden et al, in a recent review, suggest that it depends on the metabolic needs of the cell. Our understanding of metabolic pathways and their control derive mostly from the study of nondividing cells that are terminally differentiated. In these cells, the need for reductive biosynthesis is minimal, so cells extract energy most efficiently from glucose through aerobic oxidation of the glycolytic end product, pyruvate, through mitochondrial oxidative phosphorylation. What about cells that are actually dividing and differentiating? They argue that these cells have a great need for reductive biosynthesis. (Think of the need to duplicate the contents of the entire cell, which effectively increases the biomass). This would mandate that cells maximize the production of small molecule precursors for synthesis of larger molecules. These small molecule precursors include acetyl CoA for the synthesis of fatty acids for membranes, glucose-6-phosphate for the synthesis of ribose and deoxyribose for the synthesis of RNA and DNA, and a myriad of small molecules or additional metabolites arising from glycolysis and the TCA cycle.  If these small molecules, which are produced in the cytoplasm or move from the mitochondria to the cytoplasm, are removed from the energy producing pathway for reductive biosynthesis, how does the cell meet its energy needs?

One type of proliferating cell that has been well studied is the tumor cell. These cells, which have great need for reductive biosynthesis, have long been know to undergo aerobic glycolysis, and in the process produce large amounts of lactate.  This effect was observed by Warburg in 1956, who thought the effect arose through defective mitochondria in tumor cells (which is not the case). Proliferating, single cell organisms also engage in aerobic glycolysis. It now appears that proliferating, non-tumor cells from multicellular organisms do as well. Aerobic glycolysis (glycolysis in the presence or absence of dioxygen) would obviously occur most readily under adequate nutritive conditions which would be present in multicellular organisms receiving a constant stream of nutrients delivered by the blood. Under restrictive nutrient conditions, cells would undergo cell phase arrest to minimize proliferation. In contrast, differentiated and nonproliferating cells from multicellular organisms, with no need for significant reductive biosynthesis, would obtain energy most efficiently through mitochondria aerobic pathways.

A little stoichiometry will clarify the differing needs required by the pathway which leads to the most efficient use of glucose for ATP production (through converison to pyruvate and its continued conversion of carbon dioxide aerobocially) and use of glucose for reductive synthesis of the palmitic acid (16:0). The net equation for the production of 16:0 from metabolites of glucose (acetyl CoA formed from progression of glucose to pyruvate in glycolysis, and its subsequent oxidative decarboxylation to acteyl CoA in the mitochondria) is:

8 CH3(CO)SCoA + 7 ATP + 14 NADPH --> 1 palmitic acid + 7 ADP + 7 Pi + 14 NADP+

(Note: NADPH is a phosphorylated version of NADH found in the cytoplasm and is used for reductive biosynthesis instead of NADH. Reduced nicotinamide adenine dinucleotide molecules needed for reductive biosynthesis are differentiated from those produced during catabolism by being phosphorylated and by being predominantly found in a different cellular compartment (the cytoplasm compared to the mitochondria).)

From where do all the needed ATP and NADPH molecules derive? Let's consider that question starting from glucose. 

  • 1 Glucose produces around 36 ATPs from mitochondrial TCA cycle followed by oxidative phosphorylation. Hence, on a molar ratio basis, 0.2 mol of glucose are required to produce the necessary 7 mol ATP for synthesis of 1 mol of 16:0.

  • 1 Glucose produces 2 NADPH when the first product in glycolysis, glucose-5-phosphate, is withdrawn from glycolysis and moved into an alternative pathway, the pentose phosphate shunt, that produces ribose 5-phosphate for RNA and DNA production. Hence 7 mol glucose (35x the amount needed to make the required ATP) are needed to produce the required 14 mol of NADPH required to produce 1 mol of 16:0.

  • 4 Glucose molecules produce 8, 2C-CH3(CO)SCoA (with the other 8 carbon atoms originally in 8 pyruvates lost as CO2 on conversion to acetylCoA by pyruvate dehydrogenase).

Hence there is greater molar need for glucose to be used for production of the small molecule intermediates necessary for 16:0 reductive bioynthesis in proliferating cells than the molar need for glucose to produce the energy (in the form of ATP) required for 16:0 synthesis. This suggests that targeting important (but to some, "boring") enzymes involved in glycolysis and the TCA cycle (which to reiterate are the sources of the small molecule precursors for reductive biosynthesis) might inhibit tumor proliferation.

Proliferating cells have high ATP/ADP and NADH/NAD ratios which leads to feedback inhibition of important steps in energy production, including the synthesis of citrate from oxaloacetate and pyruvate in the first step of the TCA cycle. Under these conditions, citrate leaves the mitochondria where it cleaved in an ATP dependent fashion back into acetyl CoA (which can now be used for fatty acid synthesis) and oxaloacetate. To allow continued TCA activity, glutamine, an amino acid which is also metabolized in high quantities in proliferating cells, can be converted in the mitochondria to glutamic acid which after loss of ammonia forms alpha-ketoglutarate, an intermediate in the TCA cycle.  This allows continued energy production in the TCA cycle.

How much of glucose is used for energy production versus small molecule precursor production? Vander Heiden et al suggest that in proliferating and tumor cells, about 85% is used in lactate production, and 5% used in mitochondrial oxidation, while 10% is shunted for precursor production.  60% of glutamine is also used (as described above) for biosynthesis.  It would appear that lactate that results from this process is wasteful of carbon atoms that could go into reductive biosynthesis. However, it can be recycled through the Cori cycle, in which the liver converts it into glucose which is exported.      

Figure:  Metabolic Pathways in Proliferating Cells

28metabolismWarburg.gif

Feeding and Fasting: The Regulation of Storage and Breakdown of Glucose and Lipids - The Role of PPARs

We have spent little time discussing the detailed anabolic and catabolic pathways of metabolism. That is the topic of another biochemistry course. However, it should be clear that the one pathway should be activated and the other inhibited, depending on the energy state of the individual. In the well fed state (high levels of carbohydrates and lipids), glycogen, triacylglyceride, and fatty acid synthesis should be activated, while glycogen breakdown (glycogenolysis), mobilization of triglyceride reserves (breakdown of TAGs to form free fatty acids), and fatty acid oxidation should be minimized. In the fasting state, the opposite pathways should be activated.  The regulatory control of these opposing processes is complicated but PPARs have been shown to have a major role. PPARs (peroxisome proliferator-activated receptors) are nuclear receptors that are ligand-gated transcription factors. These proteins were initially discovered to be the binding target of small synthetic drugs called peroxisome proliferators. Later the relevant physiological ligands were found to include long chain polyunsaturated fatty acids, oxidized fatty acids, and eicosonoid derivatives of arachidonic acid (20:4D5,8,11,14). PPAR in the presence of ligand binds a second protein, the retinoid X receptor (RXR), which binds 9-cis-retinoic acid. The heterodimer binds to peroxisome proliferator response element in the promoter region of genes involved in lipid transport and metabolism, and activates their transcription. Given these facts, common chronic diseases with lipid abnormalities (cardiovascular disease, diabetes, obesity) would be expected to be affected by PPARs. There are three types of PPARs: a, b, and g.  Only the major two types, a and g, will be discussed.

PPAR Type location ligand activator effects
a brown adipose tissue, liver (some in kidney, heart, and skeletal muscle) long chain unsaturated fatty acid like linolenic acid, oxidized fatty acid, eicosanoids (8S-HETE, LT B4) fatty acid catabolism - FA transport, FA oxidation in peroxisomes and mitochondria
 g adipose cells, some in colon 15-deoxy-D-prostaglandin J2   storage of fatty acids - lipoprotein lipase, adipocyte FA binding protein, FA transport; acyl CoA synthase

Fatty acids are oxidized when food is scarce, but are stored as triacylglycerides when they are abundant. PPARs a and g have differential effects in the fed and fasting states:

Organ

Fed:  Synthesize FA, triacylglycerides. CHO and fat in circulation

Increased PPAR

Fasting: oxidize FA, break down triacylglycerides

Increased PPAR

Liver

(PPAR-a)

Glc taken up by liver where it can be stored as glycogen. If glycogen reserves are high, Glc is funneled through glycolysis to pyruvate then to acetyl-CoA.  Acetyl CoA then is used in the synthesis of fatty acids, which are esterifed to glycerol to form TAGs. These leave liver as VLDL (very low density lipoprotein).  Sterol response element binding protein (SREBP) levels increase, leading to increase in transcription of genes involved in above processes. 

FAs oxidized to Acetyl-CoA. Ketone bodies increase. Stimulated by increased expression of PPAR-a in fasting state. Increased FAs in liver (headed toward oxidation) might bind to PPAR-a and increase its activity.  (abcosq)

Adipocyte

(PPAR-g)

SREBP and PPAR-g levels increase (from insulin signaling).  Also SREBP activates PPAR-g gene transcription. Lead to uptake of Glc and FA into fat cells (through stimulation of breakdown of blood TAGs to fatty acids, which can be imported into fat cells. Glc through glycolysis to glyceraldehyde 3P which, with FAs, are converted to TAGs. Increased TAGs lead to leptin release by adipocytes. (This hormone leads to decreasing storage of TAGs. _(AG) SREBP and PPAR-g levels decrease. TAGs converted to glycerol and FA, mostly for export. However, some reesterifies from FA and glycerol made reverse of glycolytic pathway, called gluconeogenesis. Transcription of an important enzyme in this pathway, PEPCK, is activated under control of PPAR-g.

Drugs that bind to and either mimic (agonist) PPAR -a or -g effects are useful therapeutically in conditions characterized by lipid abnormalities (diabetes, cardiovascular disease). Drugs that bind to and activate PPAR-g (Rezulin, Avandia) can lower blood glucose levels and are used to treat type II diabetes. Drugs that activate PPAR-a (fibrates like gemfibrozil) can lower serum triglycerides (by stimulating liver fatty acid oxidation). Both drugs ultimately lower serum lipids. 

PPARs also have an effect on plasma lipoprotein (LDL, HDL) levels. Both also might have a role in inflammation, which can promote cardiovascular disease. Fibrates, which interact with PPAR-a, appear to inhibit the inflammatory response mediated by the immune system by decreasing the release of protein "hormones" or cytokines, from stimulated immune cells.