2009 cengage-wadsworth chapter 5 lipids. 2009 cengage-wadsworth introduction simple lipids –fatty...

2009 Cengage-Wadsworth

Chapter 5

Lipids


Introduction

• Simple lipids– Fatty acids– Triacylglycerols,

diacylglycerols, & monoacylglycerols

– Waxes• Sterol esters• Nonsterol esters

• Compound lipids– Phospholipids

• Phosphatidic acids• Plasmalogens• Sphingomyelins

– Glycolipids– Lipoproteins


Introduction

• Derived lipids • Ethyl alcohol


Structure & Biological Importance

• Lipids important in human nutrition:– Fatty acids– Triacylglycerols– Sterols & steroids– Phospholipids– Glycolipids


Fatty Acids

• Straight hydrocarbon chain terminating with a carboxylic acid group

• Fatty acid nomenclature– Delta () system - length, number/

position of double bonds– Double bonds counted from omega

(methyl) end


Fatty Acids

• Essential fatty acids– Linoleic acid & -linolenic acid

• n-3 fatty acids– Hypolipidemic & antithrombotic

effects– Fish oils are rich sources


Triacylglycerols (Triglycerides)

• Trihydroxy alcohol (glycerol) to which 3 fatty acids are attached by ester bonds

• Nomenclature: stereospecific numbering (sn)

• Exist as fats or oils depending on nature of fatty acid components


Sterols & Steroids

• Sterols– Monohydroxy alcohols with 4-ring

core structure called cyclopentanoperhydrophenanthrene (steroid) nucleus

– Cholesterol = animal sterol• Component of cell membranes• Precursor for steroids: bile acids, sex

hormones, adrenocortical hormones, vitamin D


Phospholipids

• Glycerophsphatides– Glycerol - core structure– Phosphatidic acid - building block– Usually have saturated FA in position

1 & unsaturated FA in position 2

• Biological roles of phospholipids– Cell membranes, source of

compounds, cell functions


Phospholipids

• Sphingolipids– 18-carbon amino alcohol sphingosine

forms backbone– 3 subclasses:

• Sphingomyelins - sphingophosphatides• Cerebrosides - glycolipids• Gangliosides - glycolipids


Glycolipids

• Occur in medullary sheaths of nerves & in brain tissue

• Cerebrosides– Ceramide linked to a monosaccharide

unit

• Gangliosides– Ceramide linked to an oligosaccharide


Digestion

• Triacylglycerol digestion– Lingual & gastric lipases– Emulsification in the stomach– Emulsification in small intestine - bile– The role of colipase

• Pancreatic lipase activation


Digestion

• Cholesterol & phospholipid digestion– Esterified cholesterol undergoes

hydrolysis to free cholesterol & a FA– C-2 FA of lecithin hydrolytically

removed to produce lysolecithin & a free FA


Absorption

• Micelles interact at brush border & lipid contents diffuse out into enterocytes

• FA > 10-12 C long re-esterified• Short-chain FA exit into portal

blood


Transport & Storage

• Topics related to transport & storage:– Lipoproteins– Role of the liver & adipose tissue– Metabolism of lipoproteins


Lipoproteins

• Apolipoproteins – Protein components

• Chylomicrons – Transport exogenous dietary lipids

• Very-low-density lipoprotein (VLDL) & low-density lipoproteins (LDL)– Transport endogenous lipids


Role of the Liver & Adipose Tissue in Lipid Metabolism

• Liver– Synthesizes bile salts– Synthesizes lipoproteins– Syntehsizes new lipids from non-lipid

precursors

• Adipose tissue– Absorbs TAG & cholesterol from

chylomicrons through lipoprotein lipase– Stores TAG


Role of the Liver & Adipose Tissue in Lipid Metabolism

• Metabolism of triacylglycerol during fasting– Adipocytes - lipolysis, release FA into

blood– Liver - produces ketone bodies,

continues to synthesize VLDL & HDL


Metabolism of Lipoproteins

• Low-density lipoprotein (LDL)– Transports cholesterol to tissues– Binds with LDL receptor on cells

• The LDL receptor: structure & genetic aberrations– Mutant cells can’t bind efficiently;

synthesize cholesterol to meet needs– Free cholesterol in the cell serves regulatory

functions



– Domains of LDL receptor• Domain 1 - furthest from membrane, contains

NH2 terminal of receptor, & rich in cysteine residues

• Domain 2 - made of 350 amino acids, possibly site of N-linked glycosylation

• Domain 3 - immediately outside plasma membrane, site of O-linked glycosylation

• Domain 4 - made of 22 hydrophobic amino acids• Domain 5 - COOH terminal end of protein that

projects into the cytoplast



– Types of LDL receptor abnormalities• Class 1 - no receptors synthesized• Class 2 - precursor synthesized but not

processed properly; fail to move into Golgi apparatus

• Class 3 - synthesized & processed, but processing faulty

• Class 4 - receptors bind with LDL but can’t cluster in the coated pits



• High-density lipoprotein (HDL)– Removes unesterified cholesterol

from cells/other lipoproteins – Returns it to the liver for excretion in

bile– Binds to receptors on hepatic and

extra-hepatic cells– Cholesterol acyltransferase (LCAT)


Lipids, Lipoproteins, & Cardiovascular Disease Risk

• Of interest regarding CVD:– Cholesterol– Saturated & unsaturated fatty acids– Trans fatty acids– Lipoprotein A– Apolipoprotein E


Cholesterol

• High HDL + low LDL = healthy• Ratios of ApoA to ApoB used to assess

CVD risk• Indiviuals respond differently to dietary

cholesterol– Absorption or biosynthesis– Formation & receptor-mediated clearance of

LDL– Rates of LDL removal & excretion


Saturated & Unsaturated Fatty Acids

• Positive correlation with CVD– Total fat– Saturated FAs– Cholesterol– Trans fat



• Negative correlation with CVD:– Monounsaturated FAs– Polyunsaturated FAs (n-3 & n-6)– n-3 fatty acids

• Interfere with platelet aggregation• Reduce release of cytokines• Reduce serum TAG concentration



• Proposed mechanisms for effects of FAs:– Suppression of bile acid excretion– Enhanced synthesis of cholesterol &

LDL– Retardation of LCAT activity or

receptor-mediated LDL uptake– Regulation of gene expression


Trans Fatty Acids

• Large amounts created through hydrogenation of PUFA

• Most abundant: elaidic acid & its isomers

• Raise LDL & cholesterol & lower HDL


Lipoprotein A [Lp(a)]

• Genetic variant of LDL– Attached to a unique marker protein

• Associated with atherosclerosis• Apo(a) is structurally similar to

plasminogen


Apolipoprotein E

• ApoE may be involved in atherogenesis

• 3 isoforms: apoE2, -E3, E4• E4 phenotype associated with

increased CVD risk


Integrated Metabolism in Tissues

• Catabolism of tracylglycerols & fatty acids– Mitochondrial transfer of acyl CoA -oxidation of fatty acids

• Energy considerations in fatty acid oxidation– Cleavage of saturated C-C yields 5

ATPs



• Formation of ketone bodies– Overflow pathway for acetyl CoA– Ketone concentration rises during

accelerated FA oxidation + low CHO intake or impaired CHO use

• Catabolism of cholesterol– Structure remains intact



• Synthesis of fatty acids– Basic process: sequential assembly of

“starter” acetyl CoA with units of malonyl CoA

– Essential fatty acids• Humans can’t introduce double bond

beyond 9 site• Lack 12 & 15 desaturases



– Eicosanoids: fatty acid derivatives of physiological significance• Precursor arachidonate

– “Cyclic” pathway (prostaglandins & thromboxanes)

– “Linear” pathway (leukotrienes)

• Prostaglandins - 20-C FAs with 5-C ring• Prostaglandins & thromboxanes are

“hormone-like” in action• Leukotrienes - potent biological actions



– Essential fatty acid in development– Impact of diet on fatty acid synthesis

• Synthesis of triacylglycerols• Synthesis of cholesterol

– Cytoplasmic sequence– Conversion of HMG CoA to squalene– Formation of choleterol from squalene


Regulation of Lipid Metabolism

• Linked to CHO status• Insulin’s presence or absence• Hormone-sensitive triacylglycerol

lipase - mobilizes fat• Hormones that stimulate lipolysis• Acetyl CoA carboxylase


Brown Fat Thermogenesis

• Brown adipose tissue - high vascularity, abundant mitochondria

• Special mitochondria promote thermogenesis at expense of ATP– Have H+ pores in inner membranes formed

of uncoupling protein (UCP)

• Thermogenesis triggered by ingestion of food or prolonged exposure to cold temperatures


Therapeutic Inhibition of Fat Absorption: Olestra & Orlistat• Orlestra

– Synthetic, non-caloric fat replacement

• Orlistat– Interferes with digestion & absorption

of dietary fat - 200 kcal deficit– Semisynthetic derivative of lipstatin– Inhibits pancreatic lipase


Ethyl Alcohol: Metabolism & Biochemical Impact

• The alcohol dehydrogenase (ADH) pathway– ADH in liver cells - NAD+-requiring

dehydrogenase - oxidizes ethanol to acetaldehyde

• The microsomal ethanol oxidizing system (MEOS)– System of electron transport associated

with SER– Tolerance - ethanol induces synthesis of

MEOS enzymes



• Alcoholism: biochemical & metabolic alterations– Acetaldehyde toxicity– High NADH:NAD+ ratio

• Accumulation of lipids & lactate

– Substrate competition• Vitamin A

– Induced metabolic tolerance



• Alcohol in moderation: the brighter side– Elevates HDL– Lowers serum lipoprotein– May suppress proliferation of smooth

muscle cells underlying the endothelium of arterial walls


Perspective 5

The Role of Lipids & Lipoproteins in Atherogenesis


Lipids/Lipoproteins in Atherogenesis

• Major components of atherogenesis:– Cells of the immune system– Oxidized or otherwise modified lipids &

lipoproteins (LDL)

• Roles of LDL– Chemoattractant for blood-borne monocytes– Causes transformation of monocytes into

macrophages– Inhibits mobility of macrophages so they are

trapped in endothelial spaces

2009 cengage-wadsworth chapter 5 lipids. 2009 cengage-wadsworth introduction simple lipids –fatty...

Documents

free cholesterol

unsaturated fa

release fa

fa of lecithin

bile acids

brush border lipid contents

adrenocortical hormones

sex hormones