Nuclear factor erythroid-derived 2-like 2 (NFE2L2 or NRF2) is a transcription factor that has a prominent role in antioxidant signaling and also influences mitochondrial bioenergetics. The NFE2L2 abbreviation is used in this review to avoid confusion with nuclear respiratory factor 2, which despite being a different protein, has overlapping function with NFE2L2 and shares the same NRF2 abbreviation . Although the mechanisms of NFE2L2 signaling are not fully elucidated , oxidative stress has a clear role in interacting with cysteine residues of Kelch-like ECH-associated protein 1 (Keap1), which decreases proteasomal degradation of NFE2L2 and thereby allows entry of NFE2L2 into the nucleus to induce transcription [351–355]. Although the influence of PGC-1α on antioxidant enzyme expression is not dependent on NFE2L2 [76, 356], PGC-1α increases NFE2L2 expression , indicating that NFE2L2 activity is influenced by perturbations in both energy and redox homeostasis. NFE2L2 primarily increases expression of antioxidant enzymes, including SOD1 , SOD2 , catalase [358–361], GPx , NQO1 [354, 359–362], GCL [359–361], GST , GSR [359–361], and Prx1 , but also increases expression of proteins involved in mitochondrial biogenesis and bioenergetics including NRF-1, NRF-2, TFAM, cytochrome c oxidase, and citrate synthase .
To encourage ketone production, the amount of insulin in your bloodstream must be low. The lower your insulin, the higher your ketone production. And when you have a well-controlled, sufficiently large amount of ketones in your blood, it’s basically proof that your insulin is very low – and therefore, that you’re enjoying the maximum effect of your low-carbohydrate diet. That’s what’s called optimal ketosis.
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Gluconeogenesis is the endogenous production of glucose in the body, especially in the liver primarily from lactic acid, glycerol, and the amino acids alanine and glutamine. When glucose availability drops further, the endogenous production of glucose is not able to keep up with the needs of the body and ketogenesis begins in order to provide an alternate source of energy in the form of ketone bodies. Ketone bodies replace glucose as a primary source of energy. During ketogenesis due to low blood glucose feedback, stimulus for insulin secretion is also low, which sharply reduces the stimulus for fat and glucose storage. Other hormonal changes may contribute to the increased breakdown of fats that result in fatty acids. Fatty acids are metabolized to acetoacetate which is later converted to beta-hydroxybutyrate and acetone. These are the basic ketone bodies that accumulate in the body as a ketogenic diet is sustained. This metabolic state is referred to as "nutritional ketosis." As long as the body is deprived of carbohydrates, metabolism remains in the ketotic state. The nutritional ketosis state is considered quite safe, as ketone bodies are produced in small concentrations without any alterations in blood pH. It greatly differs from ketoacidosis, a life-threatening condition where ketone bodies are produced in extremely larger concentrations, altering blood ph to acidotic a state.
Meanwhile, the KD induces a ketosis that is not a pathological but physiological condition occurring on a daily basis. Hans Krebs was the first to use the term “physiological ketosis” despite the common view of it as oxymoron (Krebs, 1966); this physiological condition, i.e., ketosis, can be reached through fasting or through a drastically reduced carbohydrate diet (below 20 g per day). In these conditions, glucose reserves become insufficient both for normal fat oxidation via the supply of oxaloacetate in the Krebs cycle and for the supply of glucose to the central nervous system (CNS) (Felig et al., 1969; Owen et al., 1969) (Figure (Figure1).1). It is well-known that the CNS cannot use FAs as an energy source because free FAs cannot cross the blood-brain barrier (BBB). This is why the brain normally uses only glucose. After 3–4 days without carbohydrate intake (KD or fasting) the CNS must find alternative energy sources as demonstrated by Cahill et al. (Owen et al., 1967, 1969; Felig et al., 1969; Cahill, 2006). These alternative energy sources are the ketones bodies (KBs): acetoacetate (AcAc), β-hydroxybutyric acid (BHB) and acetone and the process of their formation occurring principally in the mitochondrial matrix in the liver is called ketogenesis (Fukao et al., 2004). Usually the concentration of KB is very low (<0.3 mmol/L) compared to glucose (≅ 4 mmol) (Veech, 2004; Paoli et al., 2010). Since glucose and KB have a similar KM for glucose transport to the brain the KB begin to be utilized as an energy source by the CNS when they reach a concentration of about 4 mmol/L (Veech, 2004), which is close to the KM for the monocarboxylate transporter (Leino et al., 2001).
Because it lacks carbohydrates, a ketogenic diet is rich in proteins and fats. It typically includes plenty of meats, eggs, processed meats, sausages, cheeses, fish, nuts, butter, oils, seeds, and fibrous vegetables. Because it is so restrictive, it is really hard to follow over the long run. Carbohydrates normally account for at least 50% of the typical American diet. One of the main criticisms of this diet is that many people tend to eat too much protein and poor-quality fats from processed foods, with very few fruits and vegetables. Patients with kidney disease need to be cautious because this diet could worsen their condition. Additionally, some patients may feel a little tired in the beginning, while some may have bad breath, nausea, vomiting, constipation, and sleep problems.
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