lec 3 (mcbride) - lipids, carbohydrates part 2: roles in health and disease

maintaining homeostasis requires…

metabolic regulation that coordinates the use of nutrient pools

homeostasis adjusts…

production and consumption rates to maintain physiological levels while also meetinhg essential demands

• homeostatic mechanisms adjust these rates to achieve production = consumption to maintain a physiological concentration required for life

caloric homeostasis…

is a means of regulating energy stores

• caloric homeostasis (energy homeostasis) = the ability to maintain adequate but NOT excessive energy stores

excess energy fuels (nutrients) must be…

• if fuels are consumed in excess of energy needs → fuels are stored

• excess energy molecules ultimately converted to triacylglycerols which are stored in adipocytes

• diagram

  • fuel consumed = dietary protein, fats, and carbs

  • energy stored as triacylglycerols

  • fuel expended = AAs, fatty acids and monosaccharides oxidized in TCA cycle

excessive triacylgylcerol storage

has adverse health effects

• excess storage of triacylglycerols is great when there is scarcity of food to maintain energy supply

• continued energy storage leads to accumulation of triacylglycerols, enlarged adipocytes, and body weight gain

health consequences of increased body fat

• coronary heart disease

• type 2 diabetes

• cancers

• hypertension

• dyslipidemia (disruption of lipid metabolism)

• stroke

• liver and gallbaldder disease

• sleep apnea and respiratory problems

• osteoarthritis (degeneration of joint cartilage/bone)

• gynecological problems

• male infertility problems

energy balance

is controlled by both behavioral and biochemical factors

• behavior factors

  • diet/nutrient consumption

  • exercise

• biochemical factors

  • short term and long term signals

  • resting metabolic rate

  • hormones

caloric homeostasis

brain plays a key role in caloric homeostasis

• 2 types of signals in the GI tract, the β cells of the pancreas and fat cells

  • short term signals are active during a meal

  • long term signals report on the overall energy status of the body

• these signals target the brain’s arcuate nucleus, a group of neurons in a region of the hypothalamus

small peptide hormones

secreted from small intestine signal distal organs such as brain and pancreas

• short term signals relay feelings of satiety from gut → various regions of the brain, reducing the urge to eat

• cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) = small peptide hormones secreted into the blood by cells of the small intestine after a meal

  • bind to their respective GPCRs in peripheral neurons, relaying satiety signals

• CCK stimulate the secretion of pancreatic enzymes and bile salts from the gall bladder

• GLP-1 enhances glucose-induced insulin secretion and inhibits glucagon secretion

GLP-1 secretion…

promotes energy storage through increase in insulin secretion

• insulin promotes energy storage

  • increases glycogen synthesis and lipogenesis

  • decreases lipolysis

promotes energy storage through inhibition of glucagon secretion

• glucagon decreases energy storage

  • activates lipases to catalyze the hydrolysis of triacylglycerols → fatty acids

GLP-1 agonists

are a new line of medication for regulating blood sugar and lipid storage

• Glucagon-like peptide-1 agonist medication work by mimicking the GLP-1 hormone

  • triggering insulin release from the pancreas

  • decreasing glucagon secretion

  • decreasing rate of stomach emptying (digestion)

  • increasing feelings of fullness from eating (satiety)

leptin

in addition to insulin, leptin regulates long term control over caloric homeostasis

• insulin = signal molecule that communicates the status of glucose in the blood

  • secreted by the pancreatic β cells

• leptin = signal molecule that communicates the status of triacylglycerol stores

  • secreted by adipocytes

  • secreted in direct proportion to amt of fat present

  • binding to its receptors increases the sensitivity of muscle and the liver to insulin, stimulates β oxidation of fatty acids and decrases triacylglycerol synthesis

leptin also suppresses…

appetite by binding the leptin receptor in brain

• leptin = adipokine secreted by adipose tissue in direct relation to fat mass

• when fat mass increases → leptin inhibits appetite-stimulating peptide (NPY and AgRP) secretion while stimulating the release of appetite-suppressing hormone (MSH)

blood sugar levels

must be maintained between meals

• fasted-fed cycle = a physiological condition experienced after an evening meal and throughout the night’s fast

  • 3 stages

    • well-fed (post-prandial) state

    • early fasting (postabsorptive) state

    • refed state

• glucose homeostasis = constant blood-glucose concentration

  • maintained during the fasted-fed cycle by insulin and glucagon

postabsorptive state

occurs at the beginning of a fast

• postabsorptive (fasted) state = state that immediately follows the absorption of glucose from the previous meal blood-glucose concentration begins to drop

  • leads to decrease in insulin secretion and rise in glucagon

• glucagon

  • stimulates glycogen breakdown

  • inhibits glycogen synthesis

  • inhibits fatty acid synthesis

  • stimulates the gluconeogenic state in the liver

  • blocks glycolysis

gluconeogensis

is production of glucose from pyruvate

• pyruvate → PEP → fructose 1,6-biphosphate → fructose 6-phosphate → glucose 6-phosphate → glucose

glycolysis and gluconeogenesis

are reciprocally regulated

• phosphofructokinase = key enzyme in regulation of glycolysis

  • activated by F02,6-BP; AMP

  • inhibited by ATP; citrate

• fructose 1,6-biphosphatase = principal enzyme for controlling rate of gluconeogenesis

  • inhibited by F-2,6-BP; AMP

upon eating after a long fast…

liver will use glucose to replenish glycogen stores

• fat is processed the same in the normal fed state and refed state

• after long fast, liver does NOT initially absorb glucose from blood, leaving it for other tissues

• liver remains in gluconeogenic mode → replenishing liver’s glycogen stores

• after glycogen stores are replenished → liver processes excess glucose for fatty acid synthessi

diabetes

is a disease of disrupted glucose homeostasis resulting from insulin resistance

• diabetes mellitus = disease resulting from disruption of caloric homeostasis

  • characterized by overproduction of glucose by the liver and underutilization by other organs

  • named for common symptom of excessive urination

diabetes and glucose

diabetes leads to increased glucose elevation and slower clearance after meal

2 forms of diabetes

• type 1 diabetes (insulin dependent diabetes) = diabetes caused by destruction of the insulin-secreting β-cells of the pancreas

  • typically autoimmune disorder

  • begins before age 20

• insulin resistance = characteristic by which individuals are poorly responsive to insulin

• type 2 diabetes = diabetes caused by insulin resistance

  • arises later in life than type 1

  • obesity = significant predisposing factor

  • accounts for 90% of cases in the world

metabolic syndrome

is closely associated with type 2 diabetes

• metabolic syndrome = cluster of pathologies, including insulin resistance, hyperglycemia, and dyslipidemia (high blood triacylglycerol levels) that often develop together

  • thought to be a predecessor of type 2 diabetes

• hepatic steatosis = condition in which tissues other than adipose tissue accumulate fat

  • often occurs in liver and muscle

  • results in insulin resistance and pancreatic failure

storage capacity of adipose tissue

can be exceeded leading to lipid accumulation in other tissues

• in caloric excess, the storage capacity of adipocytes can be excessed with deleterious results

• excess fat accumulates in other tissues → results in biochemical malfunction of tissues

excess tissue triaglycerides

can disrupt signal-transduction pathways leading to insulin resistance

• excess fat accumulation in peripheral tissues, most notably muscles, can disrupt some signal-transduction pathways and inappropriately activate others

• in particular, diacylglycerols and ceramide activate stress-induced pathways that interfere with insulin signaling

  • decrease insulin signaling

  • decrease glucose uptake by transporter GLUT4

• results in tissue insulin resistance

possible health benefits of high fat, low carb ketogenic diet

• ketogenic diets = diets that promote ketone-body formation

  • used as therapeutic option for children with drug-resistant epilepsy

  • diets are rich in fats and low in carbs with adequate amounts of protein

• recent research in mice suggests ketogenic diets:

  • alter the microbiome → results in therapeutic effects

  • may extend lifespan, improve memory and maintain long-term health

nutritional ketosis occurs when…

liver produces ketones from lipid degradation

liver produces…

ketone bodies from acetyl coA when insulin signaling is low

• 3 molecules known as ketone bodies: acetoacetate, D-3-hydroxybutyrate and acetone

• liver enzymes catalyzing the ketone body formation rxns are

  • 3-ketothiolase

  • hydroxymethylglutaryl CoA synthease

  • hydroxymethylglutaryl CoA cleavage enzyme

  • D-3-hydroxybutyrate dehydrogenase

• acetoacetate spontaneously decarboxylates to form acetone

liver supplies…

ketone bodies to peripheral tissues

• during fasting or in untreated diabetics, liver converts fatty acids → ketone bodies which are a fuel source for number of tissues

• ketone-body production = especially important during starvation when ketone bodies = predominant fuel

• provides health benefits by shifting the energy balance towards increased triglyceride degradation

dietary consumption of trans fats…

increases CV disease

• changes in relative risk of coronary heart disease for each 1% energy fom carbohydrate that is isocalorically replaced with:

  • trans fatty acids (TFAs)

  • saturated fatty acids (SFAs)

  • monounsaturated fatty acids (MUFAs)

  • polyunsaturated fatty acids (PUFAs)

most dietary trans fats derive from…

industrial, partial hydrogenation of vegetable oils

• partially hydrogenated vegetable oils are typically less expensive than animal fats and have commericial advantages over some nonhydrogenated vegetable oils

  • longer shelf life

  • greater solidity at room temp

  • greater stability during repeated deep-frying at high temps

• example: margarine

  • partial hydrogenation of vegetable oil provides the soft, spreadable texture

naturally occurring unsaturated fatty acids are…

in the cis form

• if the hydrogen bonded to each of the carbons in the double bond are on the same side = cis and leads to bent molecular chain

• if 2 hydrogens are on opposite sides = trans and leads to straight chain

trans fats are formed…

by partial hydrogenation of cis fats

• hydrogenation occurs by adding hydrogen gas (H2) to oil with high pressure and heat

trans fats have numerous adverse effects…

contributing to heart disease

• dietary TFAs influence the function of multiple cell types including…

  • hepatocytes

  • adipocytes

  • macrophages

  • endothelial cells

• TFA consumption affects multiple metabolic risk factors including

  • lipid and lipoprotein levels

  • systemic inflammation

  • endothelial function

  • adiposity

  • glucose-insulin homeostasis

• TFA consumption increases risk of clinical coronary heart disease and likelihood of development of diabetes

cholesterol is an important component of…

cell membranes

phospholipids are major component of…

lipid bilayer

cholesterol molecules have a…

rigid planar steroid ring structure

cholesterol interact with…

phospholipid molecules in lipid bilayer to control membrane fluidity

• cholesterol stiffens region of the fatty acid tail

cholesterol is synthesized from…

acetyl coenzyme A

• 27 carbon atoms of cholesterol are derived by acetyl coA in 3 stage synthetic process

• cholesterol can be obtained form the diet or cells can synthesize it de novo (produce from scratch)

• liver and intestine are primary sites of cholesterol biosynthesis

• rate of cholesterol formation is mediated primarily by changes in the amount and activity of HMG CoA; the enzyme that catalyzes the synthesis of mevalonate (intermediate)

  • HMG CoA: 3-hydroxy-3-methylglutaryl CoA reductase

lipoproteins transport…

cholesterol and triacylglycerols throughout the organism

• lipoprotein particles = the means by which cholesterol and triacylglycerols are transported in body fluids → tissues for use as fuel or for storage

• fatty acids constituents of the triacylglycerol components of the lipoprotein particles are incorporated in phospholipids for membrane synthesis

• cholesterol = vital component of membranes and is precursor to steroid hormones

• cells are NOT able to degrade the steroid nucleus so cholesterol must be used or excreted by liver

lipoprotein particles consist of…

both hydrophobic and polar components

• lipoprotein particles consist of:

  • a core of hydrophobic lipids

  • shell of more-polar lipids and proteins

• protein components of lipoprotein particles (apoproteins) have 2 roles:

  • solubilizing hydrophobic lipids

  • containing cell-targeting signals

low-density lipoprotein (LDL) particles…

are the main carrier of cholesterol in circulation

• LDL = particles that are a major carrier of cholesterol in blood and regulate de novo cholesterol synthesis at peripheral tissues

  • contains a core of ~1500 cholesterol molecules esterified to fatty acids (most commonly linoleate)

  • contains a shell of phospholipids, unesterified cholesterol and a single copy of apoB-100 which is recognized by target cells

• cells outside the liver and intestine obtain cholesterol from LDL in plasma rather than synthesizing it de novo

  • process of LDL uptake is called receptor-mediated endocytosis

excess cholesterol causes…

arterial plaques, increasing risk of stroke and CV disease

• excess cholesterol collects in various tissues of the body

• excess LDL becomes oxidized and taken up by macrophages → become engorged and form foam cells

• foam cells become trapped in blood vessels and contribute to formation of atherosclerotic plaques

high-density lipoprotein particles transport…

cholesterol to liver for excretion

• HDL = particles that pick up cholesterol released into plasma → deliver to liver for excretion

• excretion occurs by converting the cholesterol biosynthetically into bile salts or by secreting it as unesterified cholesterol into bile

• in process called reverse cholesterol transport, HDL removes cholesterol from cells, especially macrophages, and returns it to liver for excretion

• when transport fails, macrophages → foam cells and facilitate the formation of plaques

• the more HDL → more readily this transport takes place and less likely that MPs will → foam cells

statins are a major class of drug for treating…

heart disease

• goal is to reduce blood cholesterol levels

• statins are competitive inhibitors of HMG-CoA reductase so block de novo synthesis of cholesterol

  • part of lovastatin structure that resembles the 3-hydroxy-3-methylglutaryl (HMG) moiety is in red

ANSWER: C → increase by 20 moles

EXPLANATION

+120

2×24 = -48

0.5×24 = -12

60 mols of fatty acids but question is asking how many triglyceride so per 1 mol of TAG = 3 mols of fatty acid

ANSWER = B; weight gain

leptin is responsible for suppressing appetite; if no leptin → no suppression of appetite → keep eating → fat

ANSWER = decrease by 19 moles

EXPLANATION

2000 × 10 = 20,000 = consumption

100 × 10 = 1000

20,000 - 1000 = 19,000 → 19,000/1000 = 19 mols

20,000 are being consumed and 1000 of that 20,000 comes from gluconeogenesis which means 19,000 comes from glycogen pools

ANSWER = PATIENT B

EXPLANATION

• pt B has a lower circulating glucose concentration which means the tissue has absorbed more glucose