Which is not belong to complex lipids?

Fat (Triglyceride) Digestion and Uptake

Ingested lipids are emulsified by bile acids. Bile acids are synthesized in the hepatocyte from cholesterol and transported through an ATP requiring transport system to the biliary canaliculus. They flow down through the biliary tract and about half of the bile acids reach the gallbladder. The bile acids, released from the gallbladder (bile) and the liver, emulsify the fat in the form of micelles that are units containing triglycerides (triacylglycerols) in the center surrounded by bile acids. Fats can be broken down by pancreatic lipase that gains access to the triglyceride through gaps between the bile salts. The formation of a micelle is shown in Fig. 9.22.

The fats are degraded by pancreatic lipase and phospholipase A2 (secreted by the pancreas and activated by trypsin) in the intestine to a mixture of monoglycerides and diglycerides. The action of pancreatic lipase is shown in Fig. 9.23. The action of pancreatic lipase releases two free fatty acids and one 2-monacyl-sn-glycerol that are rapidly absorbed through the intestinal wall. The transporter for long-chain fatty acids in the apical side of the mature enterocyte is fatty acid transporter protein 4 (FATP4). In the human, there is a family of six homologous transporters (FATP1 through FATP6) and they occur variously in all the fatty acid utilizing tissues in the body. FATP4, the only fatty acid transporter in the small intestine, is located in the apical brush border and is encoded on the human chromosome 9q34. It is a protein of 71,000 Da and contains 641 amino acids. Unsaturated fatty acids are more readily transported than saturated fatty acids. FATP4, in addition to its location in the plasma and internal membranes of the small intestine, is also found in adipocytes, brain, kidney, liver, skin, and heart. The isolated FATP4 also has the enzymatic activity of (long chain) AcylCoA synthase and the two activities of transporter and enzyme may work in concert to facilitate the influx of fatty acids across biomembranes. Although the brain contains FATP4, it does not use fatty acids as a source of energy and this requirement, when necessary, can be fulfilled by the action of glucagon on hormone-sensitive lipase (discussed later) to release free fatty acids and glycerol from stored triglycerides and glycerol can be metabolized to glucose via gluconeogenesis to feed the brain (see Fig. 6.14).

As seen from Fig. 9.23, lipase hydrolyzes at the 1 and 3 positions of glycerol. Phospholipids are degraded by phospholipase A2 at position 2 of glycerol to release free fatty acid and lysophospholipid as shown in Fig. 9.24. Complete digestion of a phospholipid is accomplished by phospholipase A1, phospholipase D, and phospholipase C in addition to phospholipase A2. These phospholipases all originate from the pancreas. The digestion products are absorbed by the intestinal mucosal cells (apical side of mature enterocytes) where resynthesis of triacylglycerides occurs.

Utilizing the Characteristics of Phospholipids

Because membranes consist largely of lipids, only lipid-soluble substances, which are hydrophobic, can pass through them. This feature is utilized by pharmaceutical companies if they want a drug to be absorbed rapidly into the bloodstream.

There are ways of getting polar substances through a membrane but these usually involve a mechanism that requires energy; it is not a passive process, and will be covered in more detail later (see Chapter 16 ‘How do drugs get into cells?’, p. 123 and Figure 31.1, p. 236).

A great deal of research is going into delivering drugs in liposomes – spherical aggregations of phospholipid bilayers. The drug is encased in the liposome, which has specially engineered qualities to make it favour attachment to a specified tissue or ‘target organ’. In this way, it is hoped that highly toxic drugs, such as those used in chemotherapy, can be delivered more specifically and safely than the more ­inefficient ‘shotgun’ approach of general medication.

TREATMENT

The therapy of disorders of lipid metabolism depends on the underlying lipoprotein abnormality and is directed toward returning the lipids to normal levels. Attempts should also be made to find any underlying secondary disease causing the hyperlipidemia so that it can be addressed. Dietary manipulation and lipid-lowering agents such as statins, fibrates, bile acid-binding resins, probucol, and nicotinic acid are the mainstays of therapy for primary hyperlipidemias, but there is no effective therapy for the normo- or hypolipemic conditions. The lipid-lowering effects of these agents have been well studied, but few studies mention the efficacy of these drugs for resolving xanthomas. Eruptive xanthomas usually resolve within weeks of initiating systemic treatment, and tuberous xanthomas usually resolve after months, but tendinous xanthomas take years to resolve or may persist indefinitely. The main goal of therapy for hyperlipidemia is to reduce the risks of atherosclerotic cardiovascular disease, whereas in patients with severe hypertriglyceridemia the goal is to prevent pancreatitis and its complications.

Surgery or locally destructive modalities can be used for idiopathic or unresponsive xanthomas. Xanthelasmas are often treated with topical trichloroacetic acid, electrodesiccation, laser therapy, and excision, but recurrences may occur. Although these therapies can be effective in clearing the xanthomas, the goal is to attempt to reverse or slow the associated atherosclerotic process (lipid-laden plaques collecting on the intima of blood vessels), the most serious complication of lipid disorders. A full discussion of therapy is beyond the scope of this chapter.

Biochemistry

Dietary considerations—Because of increasing concerns about obesity, health officials have recommended a substantial reduction in the amount of fat in the diet to less than 30% of total calories. In fact, most lipids used in vivo are synthesized from nonlipid sources. The exceptions include the fat-soluble vitamins, A, D, E, and K, and fatty acids possessing double bonds 6 carbons or less from the ω end (the ω end is opposite to the carboxyl end; e.g., linoleate, linolenate). The latter compounds are required for synthesis of the eicosanoids, a family of lipids that includes leukotrienes, prostaglandins, prostacyclins, and thromboxanes.

Digestion and Transport—Since lipids are not water soluble, they must be solubilized for digestion. This is the role of bile acids, secreted from the liver via the gall bladder. Bile acids emulsify dietary triglycerides and cholesterol esters for hydrolysis by intestinal lipases. Following uptake into the enterocyte, these fats are re-esterified to trigylcerides and cholesterol esters and packaged into chylomicrons, large lipoproteins with a density less than water. Chylomicrons are transported by the lymph and enter the bloodstream through the thoracic duct. They are rapidly cleared, due to the action of lipoprotein lipase which hydrolyzes the triglycerides to free fatty acids. The free fatty acids are used for energy production by various tissues with the excess stored in adipose tissue as triglyceride. The liver clears the remaining “chylomicron remnant”. This part of lipoprotein metabolism is often referred to as the exogenous pathway.

In the endogenous pathway of lipoprotein metabolism, the liver synthesizes and secretes very low-density lipoproteins, which are also degraded by lipoprotein lipase. The immediate product of this action is intermediate density lipoprotein (IDL) and then low-density lipoprotein (LDL), which is accumulated by liver (predominantly) and peripheral tissues by way of the LDL receptor. In the absence of an active receptor, LDL becomes oxidized and binds to a scavenger receptor on macrophages, a process that increases the risk for atherosclerosis.

Metabolism—The bulk of the lipids synthesized in vivo are derived from the two carbon precursor acetyl-Co A. The first and regulated step of fatty acid synthesis is catalyzed by acetyl-CoA carboxylase, which produces malonyl-Co A. Malonyl-CoA and acetyl-CoA are the starting substrates for fatty acid synthase, which generates palmitoyl-Co A. The latter is a starting point for further elongation and desaturation reactions. The CoA derivatives so generated are used for the formation of triglycerides and the various phospholipids, the latter of which are requisite components of membranes and lipoproteins.

Acetyl-CoA is also the precursor to sterols. In the formation of cholesterol, 15 acetyl-CoA units are required to generate the 27-carbon product. The regulated step of this pathway is HMG-CoA reductase, a primary site for drug targeting to lower cholesterol levels (HmG-CoA reductase inhibitors). Cholesterol serves as the precursor to bile acids in the liver, the regulated step being cholesterol 7-α hydroxylase. In the adrenals and gonads, cholesterol serves as a precursor to steroid hormones, via the action of cytochrome P450 enzymes. The rate-limiting enzyme of steroidogenesis is mitochondrial cholesterol 22,23 desmolase (side chain cleavage enzyme). Regulation of this pathway appears to be controlled by the transport of cholesterol into the mitochondria by a short-lived mitochondrial import factor referred to as the steroidogenic acute regulatory protein (StAR).

The degradation of fat begins with the action of hormone-sensitive lipase, which catalyzes the breakdown of triglycerides in adipose tissue. The released fatty acids are transported to the liver via albumin and then taken into mitochondria using carnitine as a carrier. Very long chain fatty acids are shortened in the peroxisomes and are released as octanoyl-CoA, which enters the mitochondria. Once in the mitochondria, fatty acyl CoAs are degraded via β-oxidation to acetyl-CoA, which can be further oxidized via the Krebs cycle. Complete degradation of fat yields about 9 Kcal/g, more than twice that derived from glycogen or protein degradation.

When the ratio of glucagon to insulin is elevated and the intracellular concentration of oxaloacetate is low, a portion of liver acetyl-CoA derived from fatty acids is shunted to ketone body synthesis. In the diabetic, the rate of this flux can become severe, resulting in ketoacidosis.

Endocrinology and signal transduction: Until a few years ago, the only lipids considered to be involved in cell signaling were steroid hormones, eicosanoids, and platelet activating factor (a water-soluble ether phospholipid). However, it is now recognized that cholesterol, fatty acids, and other dietary lipids serve as precursors for ligands that bind nuclear receptors and participate in signal transduction (for a review see Chawla et al (2001)). The nuclear receptors that bind lipid derivatives are part of a superfamily that includes the steroid hormone receptors, with the major difference that they bind their respective ligands with much lower affinity (∼10−6 M). The lipid receptors dimerize with retinoic acid receptors to regulate genes involved in lipid metabolism and transport. For example, cholesterol is metabolized by cholesterol 7-alpha hydroxylase in the liver to generate bile acids, which in turn bind to the FXR receptor. The activated FXR receptor then mediates a series of events that results in the down-regulation of CYP genes involved in bile acid synthesis (Table 1, taken from Chawla et al (2001) provides a list of lipid receptors, their ligands, and the action mediated).

Table 1.. The nuclear receptor ligand metabolic cascade. The RXR heterodimers, their ligands, and regulated target genes are shown. Question-marks (?) indicate that a member of this family has not yet been identified as a target for this ligand/receptor. Arrows denote whether the gene is up- or down-regulated by its cognate ligand. CYP, cytochrome P450; ABC, ATP-binding cassette.

Nuclear receptorLigandCYP enzymeCytosolic binding proteinABC transporterRetinoid X receptors*RXRα,β,γ9-cis Retinoic acid---PPARαFatty acids↑CYP4A1↑L-FABP↑ABCD2, ABCD3Fibrates↑CYP4A3↑ABCB4Peroxisome proliferator-activated receptorsPPARδFatty acids(?)(?)(?)CarboprostacyclinPPARγFatty acids↑CYP4B1↑ALBP/aP2(?)Eicosanoids↑H-FABPThiazolidinedionesLiver X receptorsLXRα,βOxysterols↑CYP7A1OSBPs?↑ABCA1, ↑ABCG1, ABCG4↑ABCG5, ABCG8Famesoid X receptorFXRBile salts↓CYP7A1↑IBABP↑ABCB11↓CYP8B1SXR/PXRXenobiotics↑CYP3A(?)↑ABCB1, ABCC2Xenobiotic receptorsSteroids↑CYP2CCARXenobiotics↑CYP2B(?)↑ABCC3Phenobarbital↑CYP2CEcdysone receptorEcR20(OH)-ecdysone↑26-(OH)aseHexamerins↑E23Retinoic acid receptorsRARα,β,γRetinoic acids↑CYP26A1↑CRABPII(?)↑CRBPIVitamin DVDR1,25(OH)2-vitamin↑CYP24(?)(?)ReceptorD3↓CYP27B1

*RXRs serve as common heterodimer partners with other receptors

Table 1. Lipid receptors, their ligands, and the action mediated. (Reproduced with permission from the American Association for the Advancement of Science http://www.sciencemag.org/).

Lipid diseases and pharmacology: By far the most common clinical presentation related to altered lipids is hyperlipidemia (actually lipemia), which is an important risk factor in developing atherosclerosis and heart disease. There are six types of hyperlipidemias (I, IIa, IIb, III, IV, and V), which are differentiated by the type(s) of lipids elevated in blood. Some types may be caused by a primary disorder such as a familial lipoprotein lipase deficiency. However, it must be appreciated that monogenic causes of hyperlipidemia are rare. Secondary causes of hyperlipidemia are related to disease risk factors, dietary risk factors, and drugs associated with hyperlipidemia. Disease risk factors include Type I and Type II diabetes mellitus, hypothyroidism, Cushing's syndrome, and certain types of renal failure. Dietary risk factors include dietary fat intake greater than 40% of total calories, saturated fat intake greater than 10% of total calories, cholesterol intake greater than 300 milligrams per day, habitual excessive alcohol use, and obesity. Drug risk factors include birth control pills, hormones such as estrogen and corticosteroids, certain diuretics, and beta adrenoceptor antagonists. Cigarette smoking with hyperlipidemia increases the risk for heart disease. For more information, see The Medline Information Web site at http://www.nlm.nih.gov/medlineplus/ency/article/000403.htm

The first line treatment in the management of hyperlipidemia usually involves changing the risk factors associated with diet, disease, and drugs. However, such changes often do not reduce serum lipid levels into the normal range. Pharmacological approaches include the use of statins (which competitively inhibit HMG-CoA reductase), fibric acid derivatives (which bind to the peroxisomal proliferation activator receptor PPAR and enhance catabolism of triglyceride-rich particles and reduce secretion of VLDL particles) (see Table I), bile acid resins (which block the interhepatic circulation of bile acids, thus increasing the conversion of hepatic cholesterol to bile acids), and nicotinic acid (which blocks VLDL synthesis). Recent studies indicate that statins alone can achieve the desired change in serum lipids with few side effects Henley et al (2002). There are several rare inherited diseases of lipid metabolism (e.g., Refsum's disease, adrenoleukodystrophy, various lysosomal or peroxisomal protein deficiencies), which are described in detail by Scriver and others Scriver et al (2001).

1.3.1.7 Nanostructured lipid carriers

Nanostructured lipid carriers (NLCs) are second-generation lipid carriers, which were developed to overcome the drawbacks of SLNs. NLCs have superior characteristics as compared to other lipid formulations. NLCs are crystallized lipid particles that have sizes below 100 nm that are dispersed into the aqueous phase, which contains an emulsifier. The use of NLCs as a delivery system offers various advantages as compared to other colloidal carriers. NLCs have a high drug loading of hydrophobic as well as hydrophilic drugs, high encapsulation efficiency, and improved stability (Salvi & Pawar, 2019).

NLCs offer various advantages including (Jaiswal, Gidwani, & Vyas, 2016):

Improved physical stability and enhanced dispersibility in aqueous media.

Encapsulation of both hydrophilic and hydrophobic drugs is possible with a high entrapment efficiency.

Particle size can be controlled, hence, NLCs are considered to be suitable for pulmonary delivery.

Skin occlusion can be increased by the use of NLCs.

Extended-release of drugs can be obtained by NLCs.

NLCs can penetrate the stratum corneum due to the small size of lipid particles.

NLCs are suitable for drugs that are applied via the topical route due to having lipid components that are used commercially in pharmaceutical preparations or topical cosmetics.

What is not a complex lipid?

What are the complex lipids?

What are the 4 types of lipids?

What are complex lipids give an example?