Summary of the process of digestion and absorption of lipids in the intestine (see text for details) (Source: Vander et al, 1999, p 565, fig. 17-12). In the following pages we will mainly focus on the metabolism of the simple lipids.
OXIDATION OF FATTY ACIDS
A fatty acid is completely oxidized in tissue when the primary purpose is to obtain energy.
Chemical structures of the intermediate, acyl-CoA (iii), and all final products (iv), in α-oxidation of phytanic acid in the peroxisome. Presentation of the carnitine shuttle: The four shuttle enzymes are differentially located in the mitochondrial membrane.
Dehydrogenation of acyl-CoA to trans-Δ 2 -enoyl-CoA
Hydration of trans-Δ 2 -enoyl-CoA to L-β-hydroxyacyl-CoA
Dehydrogenation of L-β-hydroxyacyl-CoA to β-ketoacyl-CoA
Thiolysis of β-ketoacyl-CoA with release of acetyl-CoA
Pathway of β-oxidation of fatty acids in mitochondria: A single passage of the acyl group through the oxidative system involves four consecutive reactions viz. The β-oxidation pathway of an unsaturated fatty acid, linoleic acid, which finally yields acetyl-CoA (refer to text below for details).
KETOGENESIS
SYNTHESIS OF KETONE BODIES
Formation of acetoacetyl-CoA
Condensation of acetoacetyl-CoA with acetyl-CoA
Production of acetoacetate and release of acetyl-CoA
UTILIZATION OF KETONE BODIES
Acetoacetate is then activated to acetoacetyl-CoA by a rather unusual enzyme CoA transferase (=thiophorase), which uses succinyl-CoA to donate CoA. Acetoacetyl-CoA is then cleaved by thiolase into 2 molecules of acetyl-CoA which are oxidized via the TCA cycle and ETS to yield CO2, H2O and ATP. Although the liver is the largest producer of ketone bodies, it cannot use them as energy fuel because hepatocytes do not have CoA transferase.
Schematic representation of the production and release of ketone bodies by the liver and their liver.
REGULATION OF KETOGENESIS
The mobilization of FFA from adipose tissue determines the [FFA] in the blood
Control on the partitioning of mitochondrial acetyl-CoA between ketogenesis and the TCA cycle in the hepatocytes determines the quantity of ketone bodies produced. When
PHYSIOLOGICAL IMPLICATIONS OF KETOGENESIS
Ketonemia and ketonuria refer to excess levels of ketone bodies in the blood and urine, respectively. Since ketone bodies are acidic, high levels deplete alkali reserves in the body and cause metabolic acidosis / ketoacidosis. The degree of ketosis is determined by measuring [ketone bodies] in the blood.
BIOSYNTHESIS OF FATTY ACIDS
DE NOVO SYNTHESIS OF FATTY ACIDS
The action of "malic enzyme" (NADP-malate dehydrogenase) converts malate to pyruvate and generates NADPH for fatty acid synthesis. Composite diagram of the pathways by which acetyl-CoA and NADPH are provided for fatty acid synthesis. Fatty acid synthesis is a cyclic pathway and involves the repeated addition of C2 units until the desired chain length is achieved.
Malonyl-CoA is the direct donor of the C2 unit which repeatedly feeds into the fatty acid synthesis pathway. Schematic representation of the dimeric multienzyme complex, fatty acid synthase: The two subunits (shown in different colors) are aligned in opposite directions. Schematic representation of the 3-domain organization of each fatty acid synthase subunit: domain 1 (blue) has acetyl transferase (AT), malonyl transferase (MT) and condensing enzyme (CE i.e. ketoacyl synthase); domain 2 (yellow) has dehydratase (DH /hydratase), enoyl reductase (ER), β-ketoacyl reductase (KR) and ACP; domain 3 (red) contains thioesterase.
All the reactions of fatty acid synthesis are carried out with the substrates attached to the enzyme complex and these two arms are carriers of acyl intermediates. This is useful in the relatively long, cyclic course of the fatty acid synthetic pathway.
Condensation
The enzyme-substrate complex is the acetyl-malonyl enzyme in which the two activated acyl groups are held in close proximity.
Reduction 1
The sequence of reactions in fatty acid (palmitic acid) synthesis: “fatty acid synthase” was shown schematically with its acyl–Cys-SH and –Pan-SH bearing arms attached to subunits 1 and 2, respectively.
Dehydration
Reduction 2
ELONGATION OF THE SATURATED FATTY ACID CHAIN
Significantly dissimilar components in the pathways are colored and generic names of enzymes are used.
SYNTHESIS OF UNSATURATED FATTY ACIDS
Mammalian desaturases can readily synthesize the ω9 family of fatty acids, but cannot introduce a double bond beyond the Δ9 fatty acyl chain. Therefore, linoleic and α-linolenic acids, which have unsaturation above C-9, cannot be synthesized in our body. We must consume them from plant sources, after which the elongase and desaturase systems can synthesize the ω6 and ω3 family of fatty acids.
Linoleate and linolenate can be synthesized in plants but not in animals; therefore they are essential fatty acids for animals.
SYNTHESIS OF PROSTAGLANDINS AND OTHER EICOSANOIDS
The main target of short-term regulation is acetyl-CoA carboxylase (ACC), the first enzyme in fatty acid synthesis. Citrate levels are high when [acetyl-CoA] is high, and such a situation is favorable for fatty acid synthesis. Citrate has a major role in shifting the metabolism of fuel components from oxidation to the synthesis of fatty acids and their storage as triglycerides.
Its inhibitory effect may be indirectly enhanced by suppression of the tricarboxylate transporter, thus preventing citrate efflux from the mitochondrion. So when blood glucose is low, fatty acid metabolism can switch from synthesis to oxidation. Insulin likely acts via an “activator protein” and an insulin-dependent protein kinase to stimulate ACC and increase fatty acid synthesis.
Long-term regulation of fatty acid synthesis is by changing the activity of the genes that control synthesis of ACC and fatty acid synthesis. Thus, prolonged fasting, high-fat diet and diabetes lead to a decrease in the enzymes, while a well-nourished state increases their amount.
METABOLISM OF TRIACYLGLYCEROLS The metabolism of triacylglycerols/triglycerides (TG) primarily involves
SYNTHESIS OF TRIGLYCERIDES
Excess carbohydrates, fat, or even protein can be metabolized for storage in our body as triacylglycerols. The main sites for TG synthesis and storage are the adipocytes, which are found in subdermal and retroperitoneal. Lipid droplets are stored in cells of the adipose tissue and, to a lesser extent, in steroid-synthesizing cells of the gonads and adrenal cortex.
As mentioned above, the liver and intestine also synthesize triglycerides, but unlike adipose tissue, they produce lipoprotein complexes within which the hydrophobic TGs can be released into the blood. Schematic diagram of lipid storage in an adipocyte: The. nucleus has been pushed to the side and the cytoplasm has been reduced. at the large lipid droplet. Inert, neutral lipids, such as triglycerides and cholesterol esters, form the main, central core of the droplet, which is surrounded by a layer of amphipathic phospholipids.
Formation of 1,2-diacyl glycerol phosphate
Dephosphorylation
Formation of triacylglycerol/triglyceride
MOBILIZATION OF STORED TRIGLYCERIDES
The mobilization of TG from adipose tissue is a function of the critical enzyme hormone-sensitive lipase (HSL). Adipose tissue releases part of the produced FFA into the blood, while the rest is converted to acyl-CoA for reuse in TG synthesis. This requires the action of glycerol kinase, an enzyme that is absent in adipose tissue and muscle but is present in other tissues such as the liver and kidney.
It is believed that a hormone, leptin, which is secreted by the adipose tissue and signals energy sufficiency, may also be important in the regulation. Schematic representation of short- and long-range recycling of triacylglycerol between adipose tissue and liver. 70% of all fatty acids released by lipolysis are re-esterified to form triglycerides, either by short-term recycling in the adipose tissue or by a systemic long-distance recycling between the liver and the adipose tissue.
Net release of free fatty acids from adipose tissue into the blood occurs only when hormones stimulate high HSL activity to the point that [FFA] exceeds the adipocyte's ability to resynthesize triacylglycerols. Degradation of VLDL by lipoprotein lipase in capillary walls makes FFA available again to adipose tissue.
METABOLISM OF COMPLEX LIPIDS
SYNTHESIS OF PHOSPHOLIPIDS
Phosphatidylserine (PS) is synthesized by exchange of polar "headgroups" and CTP is not involved. For synthesis of phosphatidylinositol (PI) and cardiolipin, CDP must bind to the hydrophobic "tail" (DG) to yield the activated intermediate CDP-DG. An ether glycerophospholipid is synthesized by replacing the acyl group at C-1 of 1-acyl DHAP with an alkyl group from a saturated alcohol.
A mixed function oxidase now introduces a double bond at C-1 in the alkyl acyl derivative, forming the plasmalogen. Overview of the steps in the synthesis of a plasmalogen: Follow the change at C-1 (majenta) from saturated acyl to saturated alkyl and then to vinylalkyl group. Freshly synthesized phospholipids travel to their intracellular destinations via transport vesicles or with specific cytosolic proteins.
They insert into the outer leaflet of the ER membrane as shown in the figure below. Their transfer to the inner leaflet of the ER membrane and to other membranes in the cell may involve flippases and special phospholipid transfer proteins.
SYNTHESIS OF SPHINGOLIPIDS (Ceramide, Cerebroside, Ganglioside, Sphingomyelin)
Galactosyl/glucosyl moieties are transferred to ceramide from their UDP-galactose/UDP-glucose form to form cerebrosides and gangliosides.
DEGRADATION OF COMPLEX LIPIDS
Gangliosides and other sphingolipids are degraded by a series of lysosomal enzymes that catalyze the gradual removal of sugar units to ultimately form ceramide. Thus, Tay-Sach disease results from the absence of hexosaminidase A, which results in ganglioside accumulation in lysosomes and causes mental retardation and death. Deficiency of sphingomyelinase results in Niemann-Pick disease, in which the accumulation of sphingolipids in the brain results in developmental abnormalities, paralysis, and early death.
METABOLISM OF CHOLESTEROL
- SYNTHESIS OF CHOLESTEROL
- SYNTHESIS OF CHOLESTERYL ESTER
- REGULATION OF CHOLESTEROL SYNTHESIS
- CIRCULATION OF CHOLESTEROL
- PRODUCTION OF STEROID HORMONES
A small percentage of cholesterol synthesized in the liver is retained in hepatocytes for incorporation into membranes. Cholesteryl esters – which are either taken up by CETP (cholesteryl ester transfer protein) into lipoprotein complexes or stored in the liver. Maintaining cholesterol homeostasis in the body is important for our well-being. Cholesterol levels depend on diet and metabolism.
A high intake of saturated fatty acids causes high cholesterol levels in the liver, while a high intake of unsaturated fatty acids. The LDLs are broken down in the lysosomes and their load of cholesterol and fatty acids is released into the cell. Disc-shaped, nascent HDL particles form in the liver and intestines and are secreted into the blood.
Depleted HDL dissociates from the hepatocytes and recirculates in the plasma to take up more cholesterol. It is the basic intermediate for the synthesis of steroid hormones in the adrenal glands and gonads.
