The biosynthesis of cholesterol in the liver and intestinal cells is a process that creates the essential lipid from acetyl CoA subunits. Much interaction and regulation exists between this endogenous synthesis process and the absorption of dietary cholesterol in the small intestine. As less cholesterol is consumed, synthesis increases in order to meet the body’s demands for the nutrient, while an increase in consumption results in the downregulation of the endogenous process (2). Canonically, the synthesis pathway is divided into three distinct segments: the synthesis of activated isoprene subunits, the condensation of these isoprene molecules to form squalene, and squalene’s cyclization into cholesterol (3) The cholesterol synthesis pathway, as divided into the three main steps listed above, is shown below (Fig. 4).
Figure 4. Schematic showing the endogenous human cholesterol biosynthesis pathway. The diagram is divided into the three main steps of the process: The synthesis of the isopentenyl pyrophosphate subunit from acetyl CoA is shown in red; squalene formation from six isoprene molecules is shown in black, while the cyclization of squalene into cholesterol is shown in blue. For simplification, only the most relevant intermediates are included. A dotted box has been drawn around the step in which HMG-CoA is converted into mevalonate, as this is the most pertinent reaction to the drug described in this paper. This step is shown in more detail in Figure 3 (adapted from reference 3).
Lipid digestion and absorption
Lipids play an important role in cell structure and metabolism. TAGs are the major storage form of energy. Cholesterol is a component of cell membranes and precursor of steroid hormones. Lipid digestion occurs at lipid water interfaces since TAG is insoluble in water and digestive enzymes are water soluble. Lipids are digested and absorbed with the help of bile salts. Products of lipid digestion aggregate to form mixed micelles and are absorbed into the small intestine. Lipids are transported in the form of lipoproteins.
Fatty acid oxidation
Fatty acids have to be activated prior to their entry into mitochondrial matrix where the enzymes of β-oxidation of fatty acids are located. Activated fatty acids are then transported from cytosol to the mitochondrial matrix with the help of carnitine transporter. Total net yield of ATP per molecule of palmitic acid is 129. Similarly oxidation of unsaturated and odd chain fatty acids also take place with additional reactions. Β-oxidation in peroxisomes involves three enzymatic reactions. Minor pathways of oxidation such as α-oxidation of branched chain fatty acids and ω-oxidation of medium and long chain fatty acids in microsomes do take place in our body.
Ketone body metabolism
Ketone bodies are acetoacetate, β-hydroxy butyrate and acetone. Ketone bodies are synthesized in the liver but they are utilized by extra hepatic tissues as fuels. Ketone bodies are accumulated in the blood if the rate of synthesis exceeds the ability of extra hepatic tissues to utilize them. This leads to excess ketone bodies in blood, excretion of ketone bodies in urine and smell of acetone in breath. All these three together are known as ketosis. In uncontrolled diabetes mellitus and starvation, ketone bodies are formed.
Our results indicate that MK-deficient cells maintain the flux through the isoprenoid/cholesterol biosynthesis pathway by elevating intracellular mevalonate levels
Figure 3. Chemical structures for reduction reaction of 3-hydroxy-3-methylglutaryl-CoA, better known as HMG-CoA, into mevalonate as catalyzed by HMG-CoA reductase. HMG-CoA is the substrate for HMGR, a key enzyme that catalyzes this committed step in the cholesterol biosynthesis pathway. Statins seek to suppress this pathway by out-competing HMG-CoA for binding in the active site of HMGR (adapted from reference 1).
The synthesis of mevalonate from HMG-CoA, which occurs during the first segment of the pathway, is regarded as the “committed step” in cholesterol biosynthesis (Fig. 3). For this reason, much of the regulation that controls this process targets the enzyme responsible for this conversion; HMGR (3). HMGR is controlled through a variety of mechanisms to ensure that proper levels of cholesterol are maintained throughout the body. This array of methods includes the ubiquitination and subsequent degradation of the enzyme complex in the endoplasmic reticulum, inactivation via phosphorylation, or prevention of the transcription and translation of the enzyme and its mRNA (4). The importance of this enzyme and the reaction it catalyzes to the entire process of cholesterol biosynthesis makes inhibition of HMGR a rational and effective target for drugs that seek to lower blood cholesterol. By blocking the committed step of cholesterol biosynthesis, statins reduce the amount of cholesterol synthesized in a similar manner as that employed endogenously.
The mevalonate pathway produces isoprenoids that are vital for diverse cellular functions, ranging from cholesterol synthesis to growth control. Several mechanisms for feedback regulation of low-density-lipoprotein receptors and of two enzymes involved in mevalonate biosynthesis ensure the production of sufficient mevalonate for several end-products. Manipulation of this regulatory system could be useful in treating certain forms of cancer as well as heart disease.
N2 - The mevalonate pathway produces isoprenoids that are vital for diverse cellular functions, ranging from cholesterol synthesis to growth control. Several mechanisms for feedback regulation of low-density-lipoprotein receptors and of two enzymes involved in mevalonate biosynthesis ensure the production of sufficient mevalonate for several end-products. Manipulation of this regulatory system could be useful in treating certain forms of cancer as well as heart disease.
AB - The mevalonate pathway produces isoprenoids that are vital for diverse cellular functions, ranging from cholesterol synthesis to growth control. Several mechanisms for feedback regulation of low-density-lipoprotein receptors and of two enzymes involved in mevalonate biosynthesis ensure the production of sufficient mevalonate for several end-products. Manipulation of this regulatory system could be useful in treating certain forms of cancer as well as heart disease.
About 40% of the bodies caloric intake is derived from lipids and almost all of these calories come from fats, the . The fatty acid composition in terms of saturation (oxidation forms) is not uniform but varies with the origin. Plant fats contain more polyunsaturated fatty acids and animal fats contain more saturated fatty acids as well as cholesterol. Polyunsaturated fats are essential for humans because animals are not able to synthesize those on their own. Most lipids, however, have metabolic functions contributing to membrane structures and signaling. (C20:4) is a fatty acid which plays a central role as precursor for prostaglandin synthesis. Phospholipids are synthesized from diacylgycerolphosphate, a negatively charged phospholipid precursor and signaling molecule itself, carrying various hydrophilic and/or charged headgroups that determine the surface charge and chemical properties of biological membrane surfaces.
Schematic of pyridine nucleotides biosynthesis and their functions. Pyridine nucleotides are involved in a wide variety of cellular functions, including energy production, metabolism, redox reactions, survival/death, and ion channels under normal and pathological conditions. Trp indicates tryptophan; Na, nicotinic acid; QA, quinolinic acid; NaMN, nicotinic acid mononucleotide; Nam, nicotinamide; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; Nampt, nicotinamide phosphoribosyltransferase; Nmnat, Nam/Na mononucleotide adenylyl transferase; NADK, NAD kinase; NaPRT, Na phosphoribosyltransferase; QAPRT, quinolate phosphoribosyltransferase; NaMNAT, nicotinic acid mononucleotide adenylyltransferase; NaAD, nicotinic acid adenine dinucleotide; NaDS, NAD synthase; Trx, thioredoxin; Nox, NADPH oxidase; GSH, glutathione; Redox, reduction-oxidation; ROS, reactive oxygen species; PARP, poly(ADP-ribose) polymerases; MART, mono-ADP-ribose transferase; cADP, cyclic ADP-ribose synthase; ETC, electron transport chain.