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J. Biol. Chem., Vol. 282, Issue 8, 6, February 23, 2007

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kresge, N. Articles by Hill, R. L. Search for Related Content PubMed Articles by Kresge, N. Articles by Hill, R. L. Related Collections Classic Articles Ballard et al. 242 (11): 2746 Reshef et al. 244 (8): 1994 Reshef et al. 245 (22): 5979 Social Bookmarking                      What's this?

Classics

The Discovery of the Glyceroneogenic Pathway: the Work of Richard Hanson

Phosphoenolpyruvate Carboxykinase and the Synthesis of Glyceride-Glycerol from Pyruvate in Adipose Tissue
(Ballard, F. J., Hanson, R. W., and Leveille, G. A. (1967) J. Biol. Chem. 242, 2746–2750)

Glyceride-Glycerol Synthesis from Pyruvate. Adaptive Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Carboxylase in Adipose Tissue and Liver
(Reshef, L., Hanson, R. W., and Ballard, F. J. (1969) J. Biol. Chem. 244, 1994–2001)

A Possible Physiological Role for Glyceroneogenesis in Rat Adipose Tissue
(Reshef, L., Hanson., R. W., and Ballard, F. J. (1970) J. Biol. Chem. 245, 5979–5984)

Richard W. Hanson was born in Oxford, New York in 1935. He attended Northeastern University in Boston and earned a B.S. in biology in 1959. Hanson was then accepted into the graduate program in biology at Brown University where he worked with Paul Fenton, studying the biochemical basis for the differences between two inbred strains of mice. He published his first paper in the Journal of Biological Chemistry (JBC) in 1960 (1), earned his M.S in 1961, and received his Ph.D. in 1963. Hanson then became an officer in the United States Army and served for 2 years at the Nutrition Laboratory at Fitzsimons General Hospital in Denver, Colorado, working on the regulation of lipid metabolism in collaboration with Gilbert A. Leveille.

In 1965, Hanson moved to Philadelphia to be a postdoctoral fellow with JBC Classics author Sidney Weinhouse (2) at the Fels Research Institute, Temple University School of Medicine. There Hanson began to collaborate with another postdoctoral fellow, F. John Ballard, on the development of hepatic gluconeogenesis in the rat. Together they developed an isotopic assay for pyruvate carboxylase and phosphoenolpyruvate carboxykinase (PEPCK-C), two of the enzymes involved in hepatic gluconeogenesis. They used their assay to determine the activity of these enzymes in different tissue samples. To their surprise, Hanson and Ballard discovered that pyruvate carboxylase is expressed in adipose tissue, a tissue that does not make glucose. To explain this, they proposed that pyruvate carboxylase played an anaplerotic role and replenished citric acid cycle anions during lipogenesis in adipose tissue (3).

Shortly after, Hanson and Ballard, along with Gilbert Leveille, found that adipose tissue also contains PEPCK-C. Several previous studies had shown that isolated epididymal fat pads could synthesize the glycerol moiety of triglyceride (glyceride-glycerol) from pyruvate in the absence of added glucose. As reported in the first JBC Classic reprinted here, Hanson, Ballard, and Leveille used [¹⁴C]pyruvate to demonstrate that glyceride-glycerol was synthesized from pyruvate in adipose tissue via a pathway that involved both pyruvate carboxylase and PEPCK-C and that the pathway proceeded via a symmetrical 4-carbon intermediate. Furthermore, they found that the conversion of pyruvate to glyceride-glycerol via this pathway increased when the animal was fasted, due in part to the induction of PEPCK-C activity that occurs in adipose tissue. They proposed that this pathway, which was later termed glyceroneogenesis (i.e. the de novo synthesis of glyceride-glycerol from precursors other than glycerol or glucose) by Eleazar Shafrir and his colleagues (4), was involved in the re-esterification of fatty acid to triglyceride in adipose tissue during fasting.

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To directly determine the pyruvate-dependent rate of esterification, Hanson, Ballard, and Reshef initially established that the amount of pyruvate incorporated into the glycerideglycerol moiety of triglycerides correlated with the amount of glycerol released from epididymal adipose tissue in vitro. As reported in the second JBC Classic reprinted here, they took the tissues from fed, 24-h fasted, or re-fed rats and established that the rate of pyruvate incorporated into the glyceride-glycerol of triglyceride was markedly increased upon fasting and decreased by re-feeding but that it always, under all experimental conditions, exceeded the rate of glycerol release. They also noted that the activity of PEPCK-C (but not pyruvate carboxylase) in adipose tissue markedly increased in response to 24-h fasting but decreased when fasting was extended to 48 and 96 h. They hypothesized that the repression of PEPCK-C activity in the adipose tissue, caused by a relatively prolonged fast, resulted from an alteration in the circulating level of some hormone (most conceivably glucocorticoids).

Hanson, Ballard, and Reshef performed further experiments using adrenalectomized rats to establish the tight correlation between changes of PEPCK-C activity, glyceroneogenesis, and the reduction of free fatty acid release by pyruvate, not only in fed, fasted, and re-fed animals but also in diabetic animals. These experiments are the subject of the last JBC Classic reprinted here. Their findings supported the role of PEPCK-C as a regulatory enzyme in the glyceroneogenic sequence and established the potential of the glyceroneogenic pathway to esterify and hence restrain free fatty acid release in the absence of glucose.

Although Hanson and his colleagues had discovered a new pathway for the formation of glyceride-glycerol from pyruvate, the physiological significance of the pathway didn't become clear until several decades later. About 10 years ago, it became apparent that glyceroneogenesis is involved in the triglyceride-fatty acid cycle. This cycle is a critical factor in regulating the amount of fatty acid that is re-esterified back to triglyceride during fasting in all mammals (and probably all vertebrates) and thus has a potential role in type 2 diabetes. More information on Hanson's recent research on glyceroneogenesis and PEPCK-C can be found in his JBC Reflections (5).

In 1966, Hanson was appointed to the faculty at Temple University and rose through the ranks to become a Professor of Biochemistry in 1975. He moved to Case Western Reserve University School of Medicine in Cleveland, Ohio in 1978, where he was appointed Professor and Chairman of the Department of Biochemistry; a position he held until 1999. He is currently the Leonard & Jean Skeggs Professor of Biochemistry at that institution.

In recognition of the discovery of glyceroneogenesis, Hanson, together with F. John Ballard and Gilbert Leveille, received the Mead Johnson Award from the American Institute of Nutrition and the Osborne Mendel Award from the same organization. Hanson is also the recipient of the Rose Award (1999) and the Merck Award (2006) from the American Society for Biochemistry and Molecular Biology (ASBMB). He was the President of ASBMB in 1999, and for the last 25 years has been an Associate Editor of the Journal of Biological Chemistry. Hanson won the Havorka Prize from Case Western Reserve University in 2001 for "exceptional achievements in teaching, research and scholarly service that benefits the community, the nation and the world," and he was the 250 Anniversary Distinguished Teaching Professor at Princeton University during the 2001–2002 academic year. He was elected to the Institute of Medicine of the National Academy of Sciences in 1987.¹

Hanson's coauthors on the Classic papers, Lea Reshef and F. John Ballard, have also had very productive careers in science. Reshef is currently a professor in the Department of Biochemistry at The Hebrew University where she focuses on the regulatory machinery of mammalian biochemical pathways, in particular those involved in the homeostasis of body energy. Ballard returned to his native Australia and worked at the Commonwealth Scientific and Industrial Research Organisation (CSIRO). He then started up three biotechnology companies, GroPep, the Cooperative Research Centre for Tissue Growth and Repair, and Primegro, and is currently helping the next generation of biotechnology pioneers through his leadership of a network, BioAngels Inc., which facilitates investments and provides mentoring to early stage bioscience companies.

FOOTNOTES

¹ Biographical information on Richard Hanson was taken from Refs. 5 and 6.

REFERENCES

1. Bernfeld, P., Nisselbaum, J. S., Berkeley, B. J., and Hanson, R. W. (1960) The influence of chemical and physicochemical nature of macromolecular polyanions on their interaction with human serum -lipoproteins. J. Biol. Chem. 235, 2852–2859[Free Full Text]
2. JBC Classics: Weinhouse, S., Medes, G., and Floyd, N. F. (1944) J. Biol. Chem. 155, 143–151 (http://www.jbc.org/cgi/content/full/280/23/e20)
3. Ballard, F. J., and Hanson, R. W. (1967) The citrate cleavage pathway and lipogenesis in rat adipose tissue: replenishment of oxaloacetate. J. Lipid Res. 8, 73–79[Abstract]
4. Gorin, E., Tal-Or, Z., and Shafrir, E. (1969) Glyceroneogenesis in adipose tissue of fasted, diabetic and triamcinolone treated rats. Eur. J. Biochem. 8, 370–375[Medline] [Order article via Infotrieve]
5. Hanson, R. W. (2005) Metabolism in the era of molecular biology. J. Biol. Chem. 280, 1705–1715[Free Full Text]
6. Reshef, L., Olswang, Y., Cassuto, H., Blum, B., Croniger, C. M., Kalhan, S. C., Tilghman, S. M., and Hanson, R. W. (2003) Glyceroneogenesis and the triglyceride/fatty acid cycle. J. Biol. Chem. 278, 30413–30416[Free Full Text]

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kresge, N. Articles by Hill, R. L. Search for Related Content PubMed Articles by Kresge, N. Articles by Hill, R. L. Related Collections Classic Articles Ballard et al. 242 (11): 2746 Reshef et al. 244 (8): 1994 Reshef et al. 245 (22): 5979 Social Bookmarking                      What's this?