Lipids Metabolism VLA 2018 17. 4. 2018 Metabolism stages Figure 24.3 • Complete oxidation – energy expenditure zisk  Fatty acids: 9 kcal/g  Sugars: 4 kcal/g  Proteins: 4 kcal/g Lipids as a energy reserve  Most of body energy is formed by oxidation of sugars and lipids.  Sugars: quick source of energy  Lipids: energy reserve  Energy reserve of lipids is much higher compared to glycogen reserve Lipids metabolism  Most of lipids metabolism products is transported fo lymph as chylomicrones.  Lipids in chylomicrones are hydrolysed by plasmatic enzymes and absorbed by cells.  For energy formation only neutral lipids are oxidized  Lipids catabolism includes two distinct pathways:  Glycerol pathway  Pathway of fatty acids Lipolysis Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2 Hepatic fructose metabolism: A highly lipogenic pathway. Fructose is readily absorbed from the diet and rapidly metabolized principally in the liver. Fructose can provide carbon atoms for both the glycerol and the acyl portions of triglyceride. Fructose is thus a highly efficient inducer of de novo lipogenesis. High concentrations of fructose can serve as a relatively unregulated source of acetyl CoA. In contrast to glucose, dietary fructose does NOT stimulate insulin or leptin (which are both important regulators of energy intake and body adiposity). Stimulated triglyceride synthesis is likely to lead to hepatic accumulation of triglyceride, which has been shown to reduce hepatic insulin sensitivity, as well as increased formation of VLDL particles due to higher substrate availability, increased apoB stability, and higher MTP, the critical factor in VLDL assembly. Acetyl CoA  Under aerobic conditions the end product of glycolysis is pyruvic acid. The next step is the formation of acetyl coenzyme A(acetyl CoA) - this step is technically not a part of the citric acid cycle, but is shown on the diagram on the top left.  Acetyl CoA, whether from glycolysis or the fatty acid spiral, is the initiator of the citric acid cycle. In carbohydrate metabolism, acetyl CoA is the link between glycolysis and the citric acid cycle.  The initiating step of the citric acid cycle occurs when a four carbon compound (oxaloacetic acid) condenses with acetyl CoA (2 carbons) to form citric acid (6 carbons).  The whole purpose of a "turn" of the citric acid cycle is to produce two carbon dioxide molecules. This general oxidation reaction is accompanied by the loss of hydrogen and electrons at four specific places. These oxidations are connected to the electron transport chain where many ATP are produced. Glycolysis Figure 24.6 Lipids Synthesis Functions of human plasma lipoproteins Lipoprotein class Origin Function Chylomicrons Intestine Transport lipids from intestine to liver and tissues Very low density (VLDL) Liver Transport lipid from tissues to liver Intermediate density (IDL) VLDL Precursor of LDL High density (HDL 2 and 3) Intestine Remove cholesterol from tissues Cholesterol – the ways of excretion. Biliary and non-biliary cholesterol. Functions of bile acids (BA) in regulation of BA, energy, glucose and lipid metabolism via farnesoid X receptor (FXR) and TGR5-mediated signaling pathways. BAT—brown adipose tissue; FGF—fibroblast growth factor; GLP-1—glucagon-like peptide 1 A wide range of Takeda-G-protein-receptor-5 (TGR5) effects. A variety of downstream effects has spawned intense interest in the therapeutic potential of TGR5 agonists for the treatment of metabolic and inflammatory diseases. GLP-1, glucagon-like peptide-1; NS, nervous system; PYY, peptide tyrosine tyrosine; T2D, type 2 diabetes. Hodge, R. J. and Nunez, D. J. (2016), Therapeutic potential of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or hype?. Diabetes, Obesity and Metabolism. doi: 10.1111/dom.12636 Lipid droplets  Storage neutral lipids, i.e. triacylglycerols (TAG) and sterol esters (SE), are stored in the form of lipid droplets (LDs) in almost all eukaryotic cells.  LDs are dynamic subcellular organelles that not only govern the storage and turnover of lipids, but also function in membrane and lipid trafficking, protein storage and degradation, and even in the replication of hepatitis C virus.  All LDs comprise a core of storage neutral lipids which are wrapped by a monolayer of phospholipids with proteins embedded. LDs are believed to originate from the endoplasmic reticulum (ER), although the exact mechanism underlying their biogenesis remains to be determined. Lipodystrophies  Heterogenic group of diseases defined as localised or generalised loss of body fat.  If localised, usually related with fat hypertrophy in other side of the body.  Usually associated with sever metabolic changes including insulin resistance, dyslipidemia and glucose intolerance.  Different phenotypes:  Familiar parcial lipodystrophy, type Dunnigan (FPLD): fat reduction on the lower part of the body, hypetrophy on the upper part  Barraquer–Simons syndrome – reverse phenotype, milder metabolic changes  Problems on the level of:  adipogenesis, insulin sensitivity, TAGs storage, lipid droplets formation, oxidative stress and fat remodellation. Cellular targets alterated by mutations in lipodystrophies A: proteins taking part in adipogenesis at the level of nuclear DNA and in insulin signal trasnduction pathway B: proteins of endoplasmatic reticulum and lipid droplets during fat storage Hyperlipidemia Signs  Atheroma- plaques in blood vessels Hyperlipidemia signs  Xanthoma- plaques or nodules composed of lipid-layden histiocytes (foamy cells) in the skin, especially the eyelids Tendenous Xanthoma Xanthoma deposits in tendon, commonly the Achilles Corneal arcus  Lipid deposit in cornea Thank you for your attention