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A Humble Hexose Monophosphate Pathway Metabolite Regulates Short- and Long-Term Control of Lipogenesis

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A Humble Hexose Monophosphate Pathway Metabolite Regulates Short- and Long-Term Control of Lipogenesis A humble hexose monophosphate pathway metabolite regulates short- and long-term control of lipogenesis Richard L. Veech* Laboratory of Metabolism and Molecular Biology, Department of Health and Human Services, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, 12501 Washington Avenue, Rockville, MD 20852 ost modern biologists and Feeding of a high-carbohydrate diet nuclear entry of ChREBP, whereas contemporary textbooks of has long been known to stimulate the phosphorylation of Thr-666 inhibited its biochemistry present the synthesis of fatty acids and to cause the binding to the LPK promoter site. This glycolytic pathway and the coordinate induction not only of the en- inhibition by ChREBP of nuclear entry M zymes of the fatty acid synthesis path- and DNA binding gave a further mecha- synthesis of fats as history where all of the relevant facts are known. An article way but also of glycolytic enzymes re- nism to the well known observation that in a recent issue of PNAS by Kosaku quired for the supply of pyruvate, the glucagon, a stimulator of cAMP produc- Uyeda and his group (1) combines new precursor of acetyl-CoA, and the en- tion, inhibits fatty acid synthesis. insights into the regulation of lipogene- zymes required for the synthesis of Just as feeding a high-cholesterol diet sis with heroic protein chemistry and an NADPH, the essential cofactor for all inhibits cholesterol synthesis, Uyeda’s elegant combination of enzymology and lipid biosynthesis. Further studies of the group next analyzed the mechanisms molecular biology. This paper describes whereby feeding of fat inhibits carbohy- how a small and ignored metabolite of drate metabolism (6). Activation of fatty acids produces AMP in a reaction of the the hexose monophosphate pathway, ϩ ϩ 3 xylulose 5-phosphate (Xu-5-P), activates Biochemistry type fatty acid ATP CoA acyl- CoA ϩ AMP ϩ PP . Using hepatocytes protein phosphatase 2A to mediate the i textbooks present transfected with ChREBP, they showed acute effects of carbohydrate feeding on that administration of the fatty acids the glycolytic pathway, as well as the glycolysis and fat acetate, octanoate, or palmitate resulted coordinate long-term control of the en- in a 30-fold increase in the concentra- zymes required for fatty acid and triglyc- synthesis as history, tion of free cytosolic AMP and a 2-fold eride synthesis. increase in the activity of the AMP- It has long been known that feeding with all of the stimulated protein kinase. AMP kinase of cholesterol suppresses cholesterol syn- phosphorylated ChREBP at a specific thesis. In the early 1990s a transcription facts known. site on the molecule and inhibited its factor designated as SREBP, a sterol binding to DNA. response element binding protein, was The unification of the long-term con- identified that regulated the transcrip- signaling involved in lipogenesis in iso- trol of fat synthesis by the transcription tion of the genes encoding a number of lated hepatocytes showed that two dis- factor ChREBP and the short-term con- the key enzymes of cholesterol biosyn- tinct transcription factors were involved. trol on glycolysis and NADPH genera- thesis, including hydroxymethylglutaryl One, SREBP-1c, was stimulated by insu- tion at the phosphofructokinase (PFK; (HMG)-CoA synthase (EC 4.1.3.5), lin. However, another DNA-binding site EC 2.7.1.11) was explained by changes HMG-CoA reductase (EC 1.1.1.88), promoting the transcription of lipogenic in the concentration of the hexose farnesyl-diphosphate synthase (EC enzymes after stimulation by high glu- monophosphate pathway metabolite Xu- 2.5.1.10), and the low-density lipoprotein cose in the absence of insulin was iden- 5-P (1). During carbohydrate feeding, receptor protein (for review, see ref. 2). tified and designated the carbohydrate- pyruvate produced in glycolysis enters SREBP also regulates the transcription response element, ChoRE (3). In a the mitochondria, where pyruvate dehy- of the gene encoding glucokinase (EC heroic feat of protein isolation, Uyeda drogenase multienzyme complex con- 2.7.1.12), an enzyme responsible for ca- and his group (4) managed to purify 100 verts it to acetyl-CoA. The acetyl-CoA talysis of the first step of hepatic glycol- ␮g of ChREBP, the protein that bound produced is condensed with oxaloac- ysis. The processing of SREBP is regu- to the ChoRE of the promoter region of etate by citrate synthase (EC 4.1.3.7) to lated by proteolysis by mechanisms the gene encoding liver pyruvate kinase form citrate, the first step in the tricar- analogous to those involved in the pro- (LPK; EC 2.7.1.40) from the livers of boxylic acid (TCA) cycle. Both fatty ac- cessing of amyloid precursor protein. 800 rats that had been fasted and then ids and cholesterol are synthesized from Cleavage of SREBP requires an activat- refed a high-carbohydrate diet. The pro- citrate produced in the mitochondrial ing protein designated SCAP and is re- tein isolated was a 100-kDa polypeptide TCA cycle and exported to the cytosol sponsible for the feedback inhibition of of the basic helix–loop–helix leucine zip- on the tricarboxylate carrier. There ci- cholesterol on sterol synthesis. It was per (bHLH-ZIP) family of transcription trate is converted to cytosolic acetyl- CoA by citrate-cleavage enzyme (EC also found that, in addition to affecting factors which bind to E-box motifs, Ϫ 4.1.3.8). HCO is added to acetyl-CoA sterol synthesis, SREBP also modulates CACGTG, within their target promot- 3 by the biotin enzyme acetyl-CoA car- the expression of some of the genes en- ers. DNA-binding activity assays, so boxylase (EC 6.4.1.2) to form malonyl- coding enzymes necessary for fatty acid called gel shifts, disclosed its presence in CoA, the first committed step of fatty biosynthesis. These findings led to the kidney and small intestine in addition to acid synthesis. The synthesis of fatty ac- conclusion that SREBP coordinates the liver. In another paper (5) Uyeda’s synthesis of the two major building group reported that ChREBP contained blocks of membranes, fatty acids and three consensus sequences for protein See companion article on page 5107 in issue 9 of volume cholesterol. Soon, however, more data kinase A phosphorylation sites and that 100. were to emerge. phosphorylation of Ser-196 inhibited *E-mail: [email protected]. 5578–5580 ͉ PNAS ͉ May 13, 2003 ͉ vol. 100 ͉ no. 10 www.pnas.org͞cgi͞doi͞10.1073͞pnas.1132039100 Downloaded by guest on September 24, 2021 COMMENTARY ids requires both malonyl-CoA, pro- duced largely from pyruvate, and reduc- ing power. That reducing power is supplied from the reactions of the malic enzyme (EC 1.1.1.39) and the first two enzymes of the hexose monophosphate pathway, glucose-6-phosphate dehydro- genase (EC 1.1.1.49) and 6-phosphoglu- conate dehydrogenase (EC 1.1.1.43). The malic enzyme and 6-phosphoglu- conate dehydrogenase reactions are both in near equilibrium with the cyto- solic free [NADPϩ]͞[NADPH] system and as such are sensitive to changes in the concentrations of their products and reactants. The reactions catalyzed by these dehydrogenases create the low- potential cytosolic free NADPϩ system, whose redox potential is Ϫ0.41 V. In comparison, the free cytosolic NADϩ system, formed by the glycolytic dehy- drogenases, glycerol-3-phosphate dehy- drogenase (EC 1.2.1.12), whose redox potential is around Ϫ0.19 V, is unable to drive the reduction of the ␤-oxoacyl- CoA to ␤-hydroxyacyl-CoA, whose half- reduction potential is Ϫ0.24 V, during fatty acid synthesis (7). The concentra- tion of malonyl-CoA and the Vmax of fatty acid synthase complex (EC 2.3.1.85) are major rate controlling steps in the process of fatty acid synthesis (8). Malonyl-CoA molecules are repeatedly added to the lengthening fatty acid chain until the complete fatty acid is released from the surface of the mul- tienzyme complex. How the disparate pathways of glycol- ysis, fatty acid synthesis, and gene tran- scription are integrated has been de- scribed in several recent papers by the Uyeda group. The enzyme PFK sits astride the intersection of the glycolytic pathway and the termination of the hex- Fig. 1. Xu-5-P is the signal for the coordinated control of lipogenesis. Feeding carbohydrate causes levels ose monophosphate pathway at the me- of liver glucose, Glc-6-P, and Fru-6-P to rise. Elevation of [Fru-6-P] leads to elevation of [Xu-5-P] in reactions tabolites fructose 6-phosphate and glyc- catalyzed by the near-equilibrium isomerases of the nonoxidative portion of the hexose monophosphate eraldehyde 3-phosphate (see Fig. 1). pathway. The elevation of [Xu-5-P] is the coordinating signal that both acutely activates PFK in glycolysis PFK activity is controlled in liver by the and promotes the action of the transcription factor ChREBP to increase transcription of the genes for the concentration of Fru-2,6-P , which is enzymes of lipogenesis, the hexose monophosphate shunt, and glycolysis, all of which are required for the 2 de novo synthesis of fat. The figure depicts the increase in enzyme transcription caused by the carbohy- produced and destroyed by a bifunc- drate response element binding protein, ChREBP, in green dashed lines. Stimulation of the Fru-2,6-kinase tional enzyme called 6-phosphofructo-2- reaction by protein phosphatase 2A (PP2A) and its stimulation by Xu-5-P are by indicated green dotted ͞ kinase Fru-2,6-P2 phosphatase (EC lines. Metabolic reactions are indicated by solid black lines. Those reactions that are reversible in vivo are 2.7.1.105͞3.1.3.46). The kinase activity is indicated with double arrows, and those catalyzing unidirectional reactions have only a single arrowhead.
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