Zonation of acetate labeling across the liver: implications for studies of lipogenesis by MIDA

While a number of studies underline the importance of anaplerotic pathways for hepatic biosynthetic functions and cardiac contractile activity, much remains to be learned about the sites and regulation of anaplerosis in these tissues. As part of a study on the regulation of anaplerosis from propionyl-CoA precursors in rat livers and hearts, we investigated the degree of reversibility of the reactions of the propionyl-CoA pathway. Label was introduced into the pathway via NaH 13 CO 3 , [U- 13 Adequate energy production via the citric acid cycle (CAC) 1 requires not only a constant supply of acetyl-CoA, but also a fairly constant pool of the catalytic intermediates which carry the acetyl groups as they are oxidized. Although the process of anaplerosis in micro-organisms was discovered in the 1960s (1), its importance for the homeostasis of mammalian cells (particularly cardiomyocytes) was recognized only in the 1980s (2, 3) (for a recent review, see Ref. 4). While the crucial role of anaplerosis for hepatic gluconeogenesis is self-evident, investigations in the heart suggested that stimulating anaplerosis from exogenous substrates could become part of the treatment of myocardial reperfusion injury and other cardiomyopathies (5-10).In a recent clinical study (11), the hypoglycemia as well as the mechanical performance of the heart and muscle of patients suffering from long chain fatty acid oxidation defects was greatly improved by replacing the fat component of their therapeutic diet, i.e. trioctanoin (a medium-even-chain triglyceride) by triheptanoin (a medium-odd-chain triglyceride). The only difference between the metabolisms of octanoate and heptanoate is the production of propionyl-CoA from the latter. In a follow-up investigation in pig hearts, propionate infusion was found to be a very effective anaplerotic substrate. Anaplerosis from 0.25 mM [U-13 C 3 ]propionate amounted to 9% of the rate of the CAC (12, 13). This led us to investigate the regulation of the propionyl-CoA pathway in livers and hearts of animals.Propionyl-CoA is formed from the activation of propionate and from the catabolism of isoleucine, valine, threonine, methionine, cholesterol, odd-chain fatty acids, and C 5 -ketone bodies (14). In mammalian tissues, the metabolism of propionyl-CoA (Fig. 1) involves (i) the formation of (S)-methylmalonyl-CoA by biotin-dependent propionyl-CoA carboxylase (15), (ii) the conversion of (S)-to (R)-methylmalonyl-CoA by methylmalonyl-CoA racemase (16), and (iii) the isomerization of (R)-methylmalonyl-CoA to succinylCoA by cobalamine-dependent methylmalonyl-CoA mutase (17-19) (for a recent review, see Ref. 20).Early in vitro work with purified enzymes revealed different degrees of reversibility of the reactions catalyzed by propionylCoA carboxylase (21, 22), methylmalonyl-CoA racemase (23), and methylmalonyl-CoA mutase (24). In the presence of a mixture of purified propionyl-CoA carboxylase, methylmalonylCoA racemase, and methylmalonyl-CoA mutase, only a few percent of the radioactivity of [ 14 C]succinyl-CoA...

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“…In non-ruminant mammals, the arterial concentration of propionate is very low (5 M in dogs (35), 30 M in pigs (13)). From Fig.…”

Section: Discussionmentioning

confidence: 99%

Assessing the Reversibility of the Anaplerotic Reactions of the Propionyl-CoA Pathway in Heart and Liver

Reszko

Kasumov

Pierce

et al. 2003

Journal of Biological Chemistry

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“…Among these gene products are a subset of all metabolic enzymes, which define the metabolic network available to support cell activities. A corollary to this is that various nutrient levels will vary by location, and levels of available nutrients will also affect which metabolic pathways are utilized by different cell types (34). In other words, there is a reciprocal interplay between the intrinsic set of metabolic enzymes expressed and their regulation by cell signaling, and extrinsic factors such as nutrient availability, which together shape the unique metabolism of each tissue (Fig.…”

Section: Implications and Perspectivementioning

confidence: 99%

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

Mayers

Heiden

2017

Cancer Research

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Understanding the genetic basis of cancer has led to therapies that target driver mutations and has helped match patients with more personalized drugs. Oncogenic mutations influence tumor metabolism, but other tumor characteristics can also contribute to their metabolic phenotypes. Comparison of isogenic lung and pancreas tumor models suggests that use of some metabolic pathways is defined by lineage rather than by driver mutation. Lung tumors catabolize circulating branched chain amino acids (BCAA) to extract nitrogen for nonessential amino acid and nucleotide synthesis, whereas pancreatic cancer obtains amino acids from catabolism of extracellular protein. These differences in amino acid metabolism translate into distinct pathway dependencies, as genetic disruption of the enzymes responsible for utilization of BCAA nitrogen limits the growth of lung tumors, but not pancreatic tumors. These data argue that some cancer metabolic phenotypes are defined by cancer tissue-of-origin and environment and that these features constrain the influence of genetic mutations on metabolism. A better understanding of the factors defining tumor nutrient utilization could be exploited to help improve cancer therapy.

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“…Deuterated water equilibrates in the whole-body pool of water. Acetate, on the contrary, is efficiently taken up and produced by the liver, and during oral administration of 13 C acetate, the enrichment in peripheral blood is considerably less than in portal blood (30). Therefore, hepatic lipogenesis incorporates in the synthesized palmitate both deuterium and 13 C, and produces VLDL-TAG labeled by both tracers.…”

Section: Calculationsmentioning

confidence: 99%

Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans

Diraison

Yankah

Letexier

et al. 2003

Journal of Lipid Research

112

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We assessed the contributions of human liver and adipose tissue de novo lipogenesis (DNL) to triacylglycerol (TAG) synthesis. Volunteers were fed a high-energy, highcarbohydrate diet (HC, n ‫؍‬ 5) or a normocaloric diet (NC, n ‫؍‬ 10). NC subjects remained in the fasting state (Study 1, n ‫؍‬ 5) or received oral glucose (Study 2, n ‫؍‬ 5) throughout the test (12 h). HC subjects remained in the fasting state

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Zonation of acetate labeling across the liver: implications for studies of lipogenesis by MIDA

Cited by 37 publications

References 21 publications

Assessing the Reversibility of the Anaplerotic Reactions of the Propionyl-CoA Pathway in Heart and Liver

Assessing the Reversibility of the Anaplerotic Reactions of the Propionyl-CoA Pathway in Heart and Liver

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans

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