脂質的代謝 脂肪酸進入細胞後會因細胞的代謝需要而進行以下的功能;

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1 脂質的代謝 脂肪酸進入細胞後會因細胞的代謝需要而進行以下的功能;
1三酸甘油酯(triacylglycerols)的合成(又稱lipogenesis), 主要合成的細胞為腸道細胞、脂肪細胞與肝細胞。 2分解產生能量 3合成細胞膜的物質

2 圖12.1 三醯基甘油在小腸的消化和吸收

3 飲食的脂肪由小腸吸收 膽鹽是一種雙極性分子，可以當作生物界面活性劑，將飲食中的脂肪轉變成膽鹽和三酸甘油酯的混合乳糜粒（圖 17-1，步驟①）。 乳糜粒的形成會增加水溶性脂肪酶在小腸 中分解脂質分子的能力，脂肪酶會將三酸 甘油酯變成單酸甘油酯（monoacylglyc- erols，又稱 monoglycerides）、雙酸甘油 酯（diacyl-glycerols，又稱 diglycerides） 、游離脂肪酸，和甘油（步驟②）。 p.690

4 圖 脊椎動物對飲食中脂質的處理過程。 P.687

5 圖 乳糜微粒的分子結構。 表面是一層頭部基團朝向水溶液的磷脂層。內部（黃色）則是由三酸甘油酯組成，佔所有質量的80% 以上。有數種脫脂脂蛋白（B-48、C-III、C-II）會從表面凸出作為乳糜微粒在吸收和代謝時的訊號。乳糜微粒的直徑大約是100 到 500 nm 。 P.687 第 17 章 脂肪酸的分解代謝

6 脂合作用(Lipogenesis) : Glycerol 3 phosphate或dihydroxy acetone phosphate與三個分子的acyl-CoA反應形成三酸甘油酯。

7 圖12.2 三醯基甘油合成

8 磷脂的分解 Phospholipase可以催化水解Phosphoglyceride分子，依據水解位置的不同，可區分為phospholipase A1、A2、C與D。 Sphingolipid 的代謝 Sphigosine是由Palmitoyl-CoA與Serine開始合成，加入acyl基後再氧化成ceramide，再與phosphatidylcholine作用形成sphingomyelin。

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10 Lipid biosynthesis Biosynthesis of fatty acids and eicosanoids
Biosynthesis of triacylglycerol Biosynthesis of membrane phospholipids Biosynthesis of cholesterol, steroids, and isoprenoids

11 脂肪酸的合成: 脂肪酸的合成位於動物細胞的細胞質中，肝臟是主要的生產工廠。 脂肪酸合成時機: 低脂肪攝取、高醣類或高蛋白攝取。
大部分脂肪酸的合成是由醣類而來。Glucose → Pyruvate (cytosol) → Pyruvate (mitochondria) → acetyl-CoA+OAA → citrate (mitochondria) → citrate (cytosol) → acetyl-CoA進行反應。

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13 脂肪酸的合成是2個碳的Acetyl-CoA一個接一個接起來的，合成的起始反應是由Aectyl-CoA carboxylase所催化:
acetyl-CoA + CO2 + ATP → Malonyl-CoA是速率決定步驟。

14 圖12.12 丙二醯輔酶A的合成

15 The acetyl-CoA carboxylase reaction

16 The mammalian FAS I Seven active sites for different reactions lie in separate domain. The mammalian polypeptide functions as a homodimer (Mr. 480,000). The subunits appear to function independently. When all the active sites in one subunit are inactivated by mutation, fatty acid synthesis is only modestly reduced.

17 The structure of fatty acid synthase type I system

18 圖12.11比較在醯基攜帶蛋白質(ACP)的與輔酶A的磷酸泛酸(phosphopantetheine)基團

19 Acyl carrier protein (ACP)
The 4’-phosphopantetheine prosthetic group of ACP serves as a flexible arm, tethering the growing fatty acyl chain to the surface of the fatty acid synthase complex while carrying the reaction intermediates from one enzyme active site to the next.

20 Sequence of events during synthesis of a fatty acid
The acetyl group of acetyl-CoA is transferred to ACP in a reaction catalyzed by MAT. The acetyl group is then transferred to the Cys-SH group of the b-ketoacyl-ACP synthase (KS). MAT: Malonyl/acetyl-CoA-ACP transferase

21 The enzyme shown in color is the one that will act in the next step.

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28 Beginning of the second round of the fatty acid synthesis cycle

29 脂肪酸生合成

30 The overall reaction for synthesis of palmitate from acetyl-CoA
7 Acetyl-CoA + 7CO2 + 7ATP → 7 malonyl-CoA + 7ADP + 7Pi 2. Acetyl-CoA + 7 malonyl-CoA + 14NADPH + 14H+ →palmitate + 7CO2 + 8 CoA + 14 NADP+ + 6 H2O 8 Acetyl-CoA + 7ATP + 14NADPH + 14 H+ → palmitate + 8 CoA + 7ADP + 7Pi + 14 NADP+ + 6H2O +

31 Subcellular localization of lipid metabolism

32 Production of NADPH

33 大量的NADPH是合成脂肪酸必需的，胞質中NADPH的來源:
1 pentose phosphate pathway (佔大部分) 2 malic enzyme

34 Shuttle for transfer of acetyl groups from mitochondria to the cytosol

35

36 Acetyl-CoA carboxylase的調控
Acetyl-CoA carboxylase包含兩條subunit(dimer)，每一條sunbit上皆有biotin。當dimer聚合成polymer後(如檸檬酸增加)，催化反應進行。當malonyl-CoA成Palmitoyl-CoA增加時聚合作用被抑制。

37 昇糖素與腎上腺素的作用會磷酸化Acetyl-CoA carboxylase導depolymeration。

38

39 脂肪酸的分解(β-oxidation)與合成的差異
1 Location(位置):脂肪酸合成位置在細胞質，β-oxidation則在粒線體與peroxisome。 2 Enzyme:催化合成與β-oxidation的酵素是不同的 3 Thioester linkage不同:脂肪酸合成acyl-carrier是ACP蛋白，而β-oxidation則是CoA-SH。 4 Electron carriers: β-oxidation可以產生NADH與FADH2，脂肪酸合成則消耗NADPH。

40 The triacylglycerol cycle

41 Glucocorticoid hormones regulate the levels of PEP carboxykinase reciprocally in the liver and adipose tissue (a biological steroid) (a synthetic glucocorticoid)

42 Glucocorticoid Acting through the glucocorticoid receptor, tissue steroid hormones increase the expression of the gene encoding PEP carboxykinase in liver, increasing gluconeogenesis and glyceroneogenesis. Stimulation of glyceroneogenesis leads to an increase in the synthesis of triacylglycerol molecules in the liver and their release into the blood. Suppress the expression of gene encoding PEP carboxykinase in adipose tissue; recycling of fatty acids declines as a result, and more free fatty acids are released into the blood. Affecting lipid metabolism in opposite ways: a lower rate of glyceroneogenesis in adipose tissue leads to more fatty acid release, whereas a higher rate in the liver leads to more synthesis and export of triacylglycerols. The net result is an increase in flux through the triacylglycerol cycle.

43 Regulation of glyceroneogenesis
PEPCK: PEP carboxykinase

44 Connection between glyceroneogenesis and diabetes
High levels of free acids in the blood interfere with glucose utilization in muscle and promote the insulin resistance that leads to type 2 diabetes. A new class of drugs called thiazolidinediones have been shown to reduce the levels of fatty acids circulating in the blood and increase sensitivity to insulin

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46 Thiazolidinediones Bind to and activate a nuclear hormone receptor called peroxisome proliferator-activated receptor g (PPARg), leading to the induction in adipose tissue of PEP carboxykinase. A higher activity of PEP carboxykinase then leads to increased synthesis of the precursors of glyceroneogenesis, which in turn increases the resynthesis of triacylglycerol in adipose tissue and reduces the release of free fatty acid from adipose tissue into blood.

47 Thiazolidinediones used to treat type 2 diabetes

48 動物中的脂肪酸代謝的調控 脂肪酸的代謝受到嚴密的控制 1 Allosteric effect
(一)Citrate 促進Acetyl-CoA → Malonyl-CoA的酵素，能促進acetyl-CoA carboxlase活性，脂肪酸的合成 (二)Malonyl-CoA 抑制Acyl-CoA進入粒線體(因為Malonyl-CoA能抑制carnitine acyltransferase I的活性。 (三)Palmitoyl-CoA : 1抑制pentose phosphate pathway。2抑制脂肪酸合成，抑制acetyl-CoA carboxlase。

49 圖12.16 細胞內的脂肪酸新陳代謝

50 2 Hormone effect 荷爾也可以長時間的影響脂肪酸的代謝，包含短時間(數分鐘內)，長時間(數小時或數天)。 1短時間(數分鐘內):荷爾蒙作用於目標細胞後引起代謝酵素的磷酸化或去磷酸化，影響關鍵酵素的磷酸化。 2長時間(數小時或數天):荷爾蒙可以改變關鍵酵素的數量，例如長時間不進食後再充足的進食，胰島素會促進lipogenesis的酵素的合成。

51 Long-Chain saturated fatty acids are synthesized from palmitate
Palmitate, the principal product of the fatty acid synthase system in animal cells, is the precursor of other long-chain fatty acids. It may be lengthened to form stearate or even longer saturated fatty acids by further additions of acetyl groups, through the action of fatty acid elongation systems present in the smooth endoplasmic reticulum and in mitochondria. Although different enzyme systems are involved, and coenzyme A rather than ACP is the acyl carrier in the reaction, the mechanism of elongation in the ER is otherwise identical to that in palmitate synthesis: donation of two carbons by malonyl-CoA, followed by reduction, dehydration, and reduction to saturated 18-carbon product, stearoyl-CoA.

52 脂肪酸的加長與去飽和反應 加長與去飽和反應可調節細胞膜的流動性(不飽和脂肪酸熔點低)，而且合成一些脂肪酸，如eicosanoids先質(arachidonic acid)；這兩種反應皆在SER中進行。 脂肪酸的加長作用是將合成或食物中的脂肪酸再加入兩個碳，碳源是malonyl-CoA。Acyl-CoA分子在Microsome的膜上進行去飽和作用。Desaturase催化O2與脂肪酸反應產生雙鍵，NADPH是電子的提供者。

53 剛合成出來的脂肪酸是飽和脂肪酸，再依細胞的需要palmitoyl-CoA能直接合成數種型式的脂質，如三酸甘油酯或磷脂質，或在ER(因為ER內有這些酵素)進行加長(elongation)與去飽和反應(desaturating reaction)。

54 Routs of synthesis of other fatty acids
Mammals cannot convert oleate to linoleate or a-linolenate (shaded pink). Linoleate and a-linolenate are essential fatty acids for mammals; they must be obtained from dietary plant material.

55 Electron transfer in the desaturation of fatty acids in vertebrates
Occurred on the lumenal face of the smooth ER Catalyzed by fatty acid-CoA desaturase, a mixed-function oxidase.

56 Routs of synthesis of other fatty acids
Mammals cannot convert oleate to linoleate or a-linolenate (shaded pink). Linoleate and a-linolenate are essential fatty acids for mammals; they must be obtained from dietary plant material.

57 Action of plant desaturases

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59 二十碳脂肪酸(eicosanoid)的代謝
許多重要的類二十碳脂肪酸是由arachidonic acid衍生而來，細胞的arachidonic acid大部分是儲存在胞膜之phosphoglyceride的第二個碳C2上。arachidonic acid由膜上釋出是合成Eicosanoid的速率決定步驟。

60 The “ cyclic” pathway from arachidonate to prostaglandins and thromboxanes
Cyclooxygenase (COX), also called prostaglandin H2 synthase,is the enzyme of the smooth ER. Aspirin (acetylsalicylate) irreversibly inactivates the cyclooxygenase activity of COX by acetylating a Ser residue and blocking the enzyme’s active site, thus inhibiting the synthesis of prostaglandins and thromboxanes. Ibuprofen, a widely used nonsteroidal antiflammatory drug (NSAID), inhibits the same enzyme.

61 圖12.D 挑選的前列腺素(prostaglandin)和前列腺凝素(thromboxane)的合成

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63 PLA2(phospholipase A2)催化phosphoglyceride釋出arachidonic acid。一些類固醇的藥物可以抑制PLA2的活性，具有抑制發炎的特性。

64 Arachidonic acid在cyclooxygenase(aspirin可抑制此酵素的活性)催化下先產生PPG2，再形成PGH2，然後再轉成PGE2、PGF2α與TXA2等衍生物。

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67 血小板結合thrombin後會釋出Arachidonic acid合成TXA2，血小板的凝集是由TXA2所啟動(thrombin是一個蛋白脢可切開可溶的血漿蛋白fibrinogen成fibrin，然後由凝血因子13(XIIIa)催化形成血塊)。

68 圖12.E 挑選的白三烯素的合成

69 ` 另外Arachidonic acid亦可經由另一個途徑轉成白三烯素
(leukotriene)，白三烯素(leukotriene)目前功能尚不清楚，但可能是一個具化學趨性或胞內訊息傳遞功能的分子。

70 磷脂質的合成 細胞膜是由雙層脂質構成，其主要組成為phospholipid與sphingolipid組成，phospholipid的合成主發生於SER與細胞質。合成Phosphatidylethanolamine開始於細胞質，ethanolamine被磷酸化，然後形成CDP-ehtanolamine，再進入SER中與DAG作用合成磷脂質。合成Phosphatidylethanolamine與Phosphatidylcholine的過程相似。

71 Biosynthesis of phosphatidic acid
The vast major way In liver and kidney

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73 圖12.17 磷脂質合成

74 神經鞘脂類新陳代謝 3'-磷酸腺-5'-磷酸硫酸(3'-phosphoadenosine-5'-phosphosulfate;PAPS)

75 圖 '-磷酸腺苷-5'-磷酸硫酸(PAPS)

76 圖12.21 神經鞘磷脂和神經鞘醣脂類的合成

77 Biosynthesis of cholesterol
Cholesterol is doubtless the most publicized lipid, notorious because of the strong correlation between high levels of cholesterol in the blood and incidence of human cardiovascular diseases. Cholesterol is an essential molecule in many animals, but is not required in the mammalian diet—all cells can synthesize it from simple precursors. The structure of this 27-carbon compound suggests a complex biosynthetic pathway, but all of its carbon atoms are provided by a single precursor—acetate. The isoprene units that are the essential intermediates in the pathway from acetate to cholesterol are also precursors to many other natural lipids.

78 膽固醇是isopentenyl pyrophosphate衍生物之一，大部分的cholesterol分子在肝中合成。其合成的步驟:
1 acetyl-CoA形成HMG-CoA 2轉換HMG-CoA → Squalene 3 Squalene → cholesterol

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80 Origin of the carbon atoms of cholesterol

81 Stage I: Synthesis of mevalonate from acetate

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83 The committed and rate-limiting step HMG-CoA reductase, an integral membrane protein of the small ER, is the major point of regulation on the pathway to cholesterol.

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86 圖12.24 由二甲基醯丙基焦磷酸和類異戊二烯焦磷酸合成鯊烯

87 圖12.25 由鯊烯可合成膽固醇

88 圖12.22 類異戊二烯的生合成

89 Overview of isoprenoid biosynthesis

90 圖12.23 膽固醇合成

91 Cholesterol has several fates
Much of the cholesterol synthesis in vertebrates takes place in the liver. A small fraction of the cholesterol made there is incorporated into the membranes of hepatocytes, but most of it is exported in one of three forms: Biliary cholesterol, bile acids, or cholesteryl esters. Bile acids and their salts are relatively hydrophilic cholesterol derivatives that synthesized in the liver and aid in lipid digestion. Cholesteryl esters are formed in the liver through ACAT that catalyzes the transfer of a fatty acid from CoA to the hydroxyl group of cholesterol, converting the cholesterol to a more hydrophobic form. Cholesteryl esters are transported in secreted lipoprotein particles to other tissues that use cholesterol, or they are stored in the liver.

92 Synthesis of cholesteryl esters

93 Structure of a low-density Lipoprotein (LDL)

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95 Lipoproteins and lipid transport

96 Reaction catalyzed by LCAT

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100 TABLE 21-2 Apolipoproteins of the Human Plasma Lipoproteins

101 Cholesteryl esters enter cells by receptor-mediated endocytosis
Each LDL particle in the bloodstream contains apoB-100, which is recognized by specific surface receptorproteins, LDL receptors, on cell that need to take up cholesterol. The binding of LDL to an LDL receptor initates endocytosis, which conveys the LDL and its receptor into the cell within an endosome. The endosome eventually fuses with a lysosome, which contains enzymes that hydrolyze the cholesteryl esters, releasing cholesterol and fatty acid into cytosol. The apoB-100 of LDL is also degraded to amino acids that are released to the cytosol, but the LDL receptor escapes degradation and is returned to the cell surface, to function again in LDL take. ApoB-100 is also present in VLDL, but its receptor-binding domain is not available for binding to the LDL receptor; conversion of VLDL to LDL exposes the receptor-binding domain of apoB-100. This pathway for the transport of cholesterol in blood and its receptor-mediated endocytosis by target tissues was elucidated by Michael Brown and Joseph Goldstein.

102 LDL膜受器 LDL受器所媒介endocytosis作例子，Brown與Goldstein闡明了LDL由細胞清除的機轉。

103 圖11.30 LDL受器

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105 FIGURE 21-42 Uptake of cholesterol by receptor-mediated endocytosis.

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107 The LDL receptor also binds to apoE and plays a significant role in the hepatic uptake of chylomicrons and VLDL remnants. If LDL receptors are unavilable, VLDL remnants and chylomicrons are still taken up by the liver even though LDL is not. This indicates the presence of a back-up system for receptor-mediated endocytosis of VLDL remnants and chylomicrons. One back-up receptor is lipoprotein receptor-related protein (LRP), which binds to apoE as well as to a number of other ligands.

108 Cholesterol biosynthesis is regulated at several levels
In mammals, cholesterol production is regulated by intracellular cholesterol concentration and by the hormones glucagon and insulin. The rate-limiting step in the pathway to cholesterol is conversion of HMG-CoA to mevalonate, the reaction catalyzed by HMG-CoA redeuctase. Regulation in response to cholesterol levels is mediated by an elegant system of transcriptional regulation of the gene encoding HMG-CoA reductase. This gene, along with more than 20 other genes encoding enzymes that mediate the uptake and synthesis of cholesterol and unsaturated fatty acids, is controlled by a small family of proteins called sterol regulatory element-binding proteins (SREBPs).

109 FIGURE 21-43 SREBP activation
FIGURE SREBP activation. Sterol regulatory element-binding proteins (SREBPs, shown in green) are embedded in the ER when first synthesized, in a complex with the protein SREBP cleavage-activating protein (SCAP, red). (N and C represent the amino and carboxyl termini of the proteins.) When bound to SCAP, SREBPs are inactive. When sterol levels decline, the complex migrates to the Golgi complex, and SREBP is cleaved by two different proteases in succession. The liberated amino-terminal domain of SREBP migrates to the nucleus, where it activates transcription of sterol-regulated genes.

110 Other regulation of cholesterol biosynthesis
Hormonal control is mediated by covalent modification of HMG-CoA reductase itself. The enzyme exists in phosphorylated (inactive) and dephosphorylated (active) forms. Glucagon stimulates phosphorylation (inactivation), and insulin promotes dephosphorylation, activating HMG-reductase and favoring cholesterol synthesis. High intracellular concentrations of cholesterol activate ACAT, which increases esterification of cholesterol for storage. A high cellular cholesterol level diminishes transcription of the gene that encodes the LDL receptor, reducing production of the receptor and thus the uptake of cholesterol from the blood.

111 FIGURE Regulation of cholesterol formation balances synthesis with dietary uptake. Glucagon promotes phosphorylation (inactivation) of HMG-CoA reductase; insulin promotes dephosphorylation (activation). X represents unidentified metabolites of cholesterol that stimulate proteolysis of HMG-CoA reductase.

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113 Lovastatin treatment lowers serum cholesterol by as much as 30% in individuals having one defective copy of the gene for LDL receptor. When combined with an edible resin that binds bile acids and prevents their reabsorption from the intestine, the drug is even more effective.

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115 Inhibitors of HMG-CoA reductase

116 類固醇激素的合成 在desmolase催下cholesterol轉成pregnenolone， pregnenolone被輸送至ER再轉成黃體素(progesterone)。Pregnenolone與progesterone是合成所有類固醇的先質(precursor)。黃體素是一種雌激素，由卵巢分泌，在懷孕初期黃體素被大量合成，它可抑制平滑肌的收縮，提高受精卵的著床率。

117 圖12.26 黃體酮合成

118 圖12.27 挑選的類固醇合成

119 腦下垂體(pituitary gland)能分泌ATCH能結合adrenal cell 促進21-hydrooxylase、17-α-hydroxylase的合成(adrenal cortex)。
Aldosterone:與離子平衡有關 Cortisol:促進肝中gluconeogenesis、lipogenesis與amino acid uptake。

120 膽固醇的分解 膽固醇與其類似物質(類固醇)並無法分解成小分子，它們會轉成水溶性較佳的衍生物排出。分解與除去膽固醇最重要的機制是合成膽酸，催化cholesterol轉成7-α-hydrocholesterol的反應是合成膽酸的速率決定步驟。催化此反應的酵素稱7-α-hydrolase。

121 圖12.28(a)膽酸(cholicacid)的合成

122 膽酸可以轉換成膽鹽，這個反應是一種Conjugation reaction「經由加入一些可溶的基團(group)，增加分子的溶解度」。共軛反應(Conjugation reaction)可以促進分子的溶解力(因加入一些易於水的物質，大部分的膽酸被加上glycine或taurine。膽鹽是膽汁主要的成份，由肝臟生成，具有幫助脂質消化的作用。

123 圖12.28(b)膽鹽甘胺膽酸(glycocholate)的合成

124 圖12.29 甘胺酸和牛磺酸的結構