Passage Myalgic encephalopathy (ME), or chronic fatigue syndrome (CFS), is a physiological disease that affects 0.15% of the human population. Compared with healthy individuals, persons with ME experience reduced phospholipid levels, muscular degeneration, urinary urgency, and other symptoms that contribute to a lower quality of life. Studies in resting subjects have yielded inconsistent data and failed to identify a unique metabolic defect in patients with ME.Analyzing the blood plasma of male and female patients with ME, physicians have observed that male patients display elevated levels of 3-methylhistidine, a marker of protein catabolism. Researchers expanded this finding by measuring the serum concentration of amino acids in blood samples obtained from nonfasting ME patients and healthy controls. Amino acids were classified into separate categories according to their metabolic intermediates.Table 1 Classification of Amino Acids in Blood Plasma Figure 1 Serum concentrations of amino acids in patients with ME and healthy controls (HC)Next, researchers hypothesized that the inhibition of pyruvate dehydrogenase (PDH) and impairment of fatty acid oxidation were responsible for the fluctuations in amino acid levels. PDH function and lipid metabolism were studied in peripheral blood mononuclear cells (PBMCs) by measuring the gene expression of proteins within regulatory pathways. Researchers monitored the mRNA levels of the inhibitor pyruvate dehydrogenase kinase 1 (PDK1) and of sirtuin 4 (SIRT4), which removes lipoic acid groups from the PDH complex. They also examined lipid metabolism by measuring the mRNA levels of peroxisome proliferator-activated receptor-α (PPARα), a transcription factor that upregulates the uptake of fatty acids. The mRNA level of each protein in PBMCs of patients with ME was evaluated against healthy controls, as shown in Figure 2. Figure 2 Gene expression of PDK1, SIRT4, and PPARα in PBMCs Adapted from Fluge Ø, Mella O, Bruland O, et al.. JCI Insight. 2016;1(21):e89376. -Lipids serve as energy stores for healthy patients and patients with ME. If both groups were fed the same diet, would the rate of lipid synthesis after a meal be faster in healthy individuals or in patients with ME?

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11ecba2d_0e2b_5be8_a3bf_9f724cc04a26_MD0008_00 The reactions involved in lipid synthesis are sensitive to hormones, such as insulin and glucagon, that control blood sugar (glucose) levels. Insulin reduces blood sugar levels by increasing glucose uptake and storage, whereas glucagon increases the production of glucose and its release into the bloodstream. Ongoing digestion after a meal leads to high blood sugar levels that induce the release of insulin and the suppression of glucagon production. Liver cells, in particular, respond to insulin by increasing their rates of lipid synthesis and mobilization. In the mitochondria, insulin activates pyruvate dehydrogenase (PDH), which converts pyruvate into acetyl-CoA. The accumulated acetyl-CoA is transported to the cytoplasm by combining with oxaloacetate to form citrate, which can exit the mitochondria. In the cytoplasm, citrate is converted back to acetyl-CoA and oxaloacetate. Insulin activates both acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), which convert acetyl-CoA to malonyl-CoA and catalyze the synthesis of 16-carbon fatty acid chains from malonyl-CoA, respectively. According to the passage, PDH has a lower activity in patients with ME than in healthy individuals. Consequently, even if insulin binds to liver cells after a meal, the pyruvate produced from glucose is not efficiently converted into acetyl-CoA and does not contribute to fatty acid synthesis. In contrast, healthy individuals would have a greater response to insulin because they have functional PDH that produces higher quantities of acetyl-CoA. Therefore, the transport of acetyl-CoA to the cytoplasm is stimulated in healthy individuals, who have a faster rate of lipid synthesis. (Choice A) Glucagon reduces the rate of lipid synthesis by inhibiting acetyl-CoA carboxylase. (Choice B) The digestion of chylomicrons (globules of protein and lipids) depends on the activity of lipoprotein lipase, which is not tested in the experiment. (Choice D) Insulin inhibits the enzyme hormone-sensitive lipase in adipocytes (fat cells) which breaks down triacylglycerides into fatty acids and glycerol. Therefore, few fatty acids would be able to contribute to lipid synthesis. Educational objective: Insulin stimulates lipid synthesis by activating the major enzymes involved in fatty acid production: Pyruvate dehydrogenase complex, acetyl-CoA carboxylase, and fatty acid synthase. PDH converts pyruvate produced from glucose into acetyl-CoA, which is transported to the cytoplasm for fatty acid synthesis.

Passage Myalgic Encephalopathy (ME), or Chronic Fatigue Syndrome (CFS), Is a a Physiological