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Lecture 27

Prometheus & the Regenerating Liver

- Prometheus: Greek God that stole fire from Zeus, gave it to humans; as punishment for this insubordination, Zeus had Prometheus bound to a rock
- every day an eagle (or vulture) came and at his liver, which re-grew during the night, only to be eaten again the next day; the liver is perhaps the only organ which can regenerate itself

The Liver

- liver: largest single organ in the body (lies below diaphragm)

Function Unit of the Liver

- the liver lobule
- adult liver has 50,000 to 100,000 lobules
- lobules made of plates of cells radiating from a central vein

Structure of the Liver

- the lobule is built around a center vein which empties into the hepatic vein, then vena cava
- made of cellular plates (hepatic plate) 2 cells thick, which radiate from central vein like spokes
- venous blood form GI tract flows from hepatic portal vein to central vein through Hepatic Sinusoids, which run btwn plates
- hepatic sinusoids lined with
1. Typical endothelial cells
2. Kupffer cells: macrophages

- endothelial cell lining has large pores which empty into the "space of Disse" : perisinusoidal spaces, which empty into lymphatic vessels
- blood from intestinal capillaries carrying products of digestion do not pass directly into general circulation but go through liver first, fxn is to cleanse blood
- bile produced by hepatocytes is released into bile canaliculi, passes to hepatic duct, common bile duct, and into the duodenum

- important structures to know (figure): duodenum, common bile duct, hepatic duct, bile canaliculi

Blood Flow of the Liver

- Blood flow: liver is a low pressure, high volume system
- 1050ml/min flow in thorugh portal vein + 300ml/min thorugh hepatic artery
- so 1350 ml/min = 27% resting cardiac output
- in portal vein pressure runs appx 9mmHg
- in hepatic vein pressure is near 0mmHg

Cirrhosis of the Liver

- Cirrhosis of liver involves replacing liver cells with fibrous tissue
- This contracts around vessels, increasing resistance of blood flow thorugh liver
- Commonly due to long-term alcohol abuse, also ingestion of poisons, viral infections

Blood reservoir of the Liber

liver fxns as a blood reservoir, holding up to 450 mls or 10% of blood

High Lymph Flow

High Lymph Flow: about half of all lymph is produced in the liver

Regeneration of the Liver

- Regeneration: the liver is able to regenerate itself after tissue loss
- "partial hepatectomy" can remove up to 70% of liver tissue, but this can be replaced in 5-7 days
- believed to be (partly) under control of hepatocyte grouth factor (HPC), other growth factors

Macrophage System

- Macrophage system: blood always picks up colon bacilli in the intestines
- as blood passes through liver, bacteria is removed by Kupffer cells, which are macrophages, serve to cleanse the blood as it passes
- normally no bacteria left as blood leaves liver

Metabolic Functions

- Carbohydrate Metabolism
1. Storage of glycogen
2. Conversion of galactose, fructose to glucose
3. Gluconeogenesis
4. Carb metabolism

- Fat Metabolism
1. Oxidation of fatty acids for energy
2. Synthesis of cholesterol, phospholipids
3. Synthesis of fat from protein and carbs

- Protein Metabolism
1. Deaminaiton of amino acids
2. Formation of urea
3. Formation of plasma proteins
4. Synthesis of compounds from amino acids

other metabolic functions:
- store vitamins: D, B12, A
- store iron in form of ferritin
- produce plasma proteins which act as clotting factors (fibrogen, prothrobin, Factor VII, IX, X)
- remove drugs, hormones from blood

Bilirubin

- In addition to bile salts, other substances excreted in bile for elmination in feces
- Bilirubin: final end product of hemoglobin degradation
- important clinical tool for diagnosis of hemolytic blood diseases and liver diseases

RBC Break Down

- RBCs have appx 120 day life-span, then become fragile and rupture
- tissue is phagocytized by reticuloendothelial system into:
1. globin
2. heme

- heme is broken into:
1. "free iron": transported by transferring
2. Pyrrole nuclei (ring of pyrrole groups) → biliverdin → "free bilirubin"
- the free bilirubin in plasma is bound by albumen, absorbed by hepatic cells, released from albumin and conjugated to glucuronic acid to form bilirubin glucuronide
- this is excreted into bile and into intestines, some becomes urobilinogen, some reabsorbed, some lost in urine, most lost in feces
- there it is converted to urobilinogen, some reabsorbed into blood to be re-excreted into intestines, some (5%) excreted in urine
- exposure to air convert urobilinogen to urobilin (in expelled urine)
- in feces, urobilinogen is oxidized into stercobilinogen

Jaundice

yellow tint to tissues, due to excess bilirubin in extracellular fluids from

Bilirubin Formation and Excretion

1. Hemolytic Jaundice: due to increased loss of RBCs beyond excretion capacity, or
2. Obstructive jaundice: due to blocked bile ducts (gallstones, tumor) or damaged liver cells (hepatitis)
- Bilirubin cannot pass from blood to small intestines
- Most present in plasma is conjugated form

Calories (cap "C") and Table 71-1

- 1 Calories (cap "C") = 1 kilocalorie
- table 71-1
- Dietary Balance: E available from foods
- Physiologically available E: (E in Calories form 1 gram)
- Avg American gets 15% of E from protein, 40% from fat, 45% from carbs
- Non-Western diets may contain 20% from fats and proteins together
- Carb Calories = 4
- Fat Calories = 9
- Protein Calories = 4

- E.g. Apples (practice calculation)
- % protein = 0.3
- % fat = 0.4
- % carb = 14.9
- Calories per 100 grams = 64

Dietary Balance: E available from Foods

- Daily Requirements: body degrades 20-30 gms protein per day, so daily intake needs to run 30-50 gms/day; some proteins are "partial proteins," missing certain essential amino acids

Caloric Needs

- Sedentary person appx 2,000 Calories daily
- "Athletes & Laborers" appx 6,000-7,000 Calories daily
- MRE (military meals): 1200 Calories

Overdependence on a single protein source and Kwashiorkor

- Overdependence on single protein source: Corn has little to no tryptophan
- Overdependence on cornmeal can produce "kwashiorkor": failure to grow, lethargy, edema
- Sudanese children present with swollen bellies, typical symptom of Kwashiokor

Hypothalamus

- densely complicated structure which is involved in regulation of many of the basic metabolic processes, or at least the upper neuronal contribution to these processes
- Receives neural signals from GI tract carrying sensory info such as
- stomach, distention
- chemical signals from nutrients in circulation in blood
- GI hormones, hormones from adipose tissue...
- Dense, very complicated structure
- Strategically position to monitor various physiological processes
- BBB is different in hypothalamus b/c "fenestrated" or "leaky" and allows various hypothalamic nuclei direct contact with circulation, something not ofund in other parts of the CNS
- Positioned along 3rd ventricle and that similar to the compromise in the BBB, hypothalamic neurons have access to CSF beyond that seen in other parts of the brain

Lateral Nuclei of the Hypothalamus

- serves as "feeding center"
- Stim causes hyperphasia, initiates or motivates search for food
- Lesions result in loss of appetite

Ventromedial Nucleus of Hypothalamus

- serves as "satiety center"
- Stim causes satiety and refusal to eat, lesions can cause overeating and obesity

Role of Hypothalamus in Food Intake Regulation (anorexigenic & Orexigenic)

- The neural circuitry involved in the regulation and balance of energy consumption has been intensely studied and while a lot of details have been discovered, the overall system remains very poorly understood
- Looking at table 71-2 in the text, there is a list of neurotransmitters and hormones, some are:
a. anorexigenic, meaning they inhibit feeding, and some are
b. orexigenic, meaning they stimulate or increase feeding

Two Types of Neurons in the Arcuate Nucleus

- The circuitry and the chemicals involved in feeding regulation are very complex, but the text focuses on two groups of neurons in the arcuate nucleus, a structure located along the base of the 3rd ventricle
- Two types of neurons:

1. POMC (pro-opiomelanocortin) neurons:
- which produce α-MSH (melanocyte-stimulating hormone) & CART (cocaine and amphetaimine related transcript)
- these neurons project to the PVN (paraventricular N), where aMSH is released on MCR3 and MCR4 receptors (melanocortin receptors)
- The PVN neurons project to N Tractus Solitarius with the effect of increasing sympathetic tone and energy expenditure
- So, activating the POMC neurons results in decreased food intake and increased energy expenditure = anorexegenic
- MCR4 mutations in humans results in obesity


2. Neurons producing NPY ( neural peptide Y) and AGRP (agouti-related protein):
- These neurons are orexigenic, activation leads to increased feeding and decreased energy expenditure
- AGRP acts as an antagonist of MRC3 and MRC4. NPY is released in arcuate n by orexigenic neurons when energy stores are low

What stimulate and/or inhibit the Arcuate Nucleus Neurons (two types)

1. POMC neurons:
- Insulin, leptin , CCK stimulate POMC/CART system

2. NPY & AGRP neurons:
- Insulin, leptin , CCK inhibit NPY & AGRP system
- Ghrelin- a stomach hormone- stimulates NPY/AGRP system

Summary of Anorexigenic and Orexigenic Systems

1. Anorexigenic:
- POMC neurons in arcuate →
- alphaMSH and CART →
- act on MCR3 and MCR4 receptors in PVN →
- PVN projects to N Tractus Solitarius →
- Increase in sympa tone, E expenditure, decrease in food intake
** stimulated by insulin, leptin, CCK

2. Orexigenic:
- AGRP and NPY neurons in arcuate →
- NPY acts as antagonist of MRC3 and MRC4 →
- Decreased sympa tone, decrease in E expenditure, increase in food intake
** Inhibted by insulin, leptin CCK
** Stimulated by Ghrelin

Regulation of Feeding: Short Term

Short Term:
- Gastrointestinal filling: distention of GI tract produces inhibitory signals via vagi
- Cholecystokinin (CCK): fat entering the duodenum induces CCK release, decreases feeding through activation of melaocortin pathway
- Ghrelin: released by oxyntic cells in stomach & intestine
- Levels rise during fasting, fall after meal
- Oral receptors: Oral sensations are monitored, measure quantity of food
- Experimental preparations using esophageal 'fistula' show animals will stop eating after a regular meal-size amount of food

Regulation of Feeding: Long Term

Long Term:
- Glucostatic Theory: lowering of circulating glucose causes hunger
- Elevated glucose levels increase firing in satiety center in ventrolateral & Paraventricuylar hypothalamus, decreases firing in hunger centers
- Aminostaic Theory: lowering of amino acids causes hunger
- Lipostatic theory: lowering levels of lipids causes hunger
- Temperature: exposure to cold induces increased eating, hot weather reduces eating
- Adipose tissue feedback (leptin)

Adipose Tissue Signals: Role of Leptin

- Adipocytes (fat cells) release leptin
- Circulating level are in proportion to adipose levels
- Leptin crosses BBB, binds to receptors in hypothalamus, esp POMC neurons in arcuate n. ad PVN.

- Receptor binding causes:
1. Decrease in activity in appetite stimulating NPY and AGRP cells
2. Increase in other appetite suppressing hypothalamic factors (e.g. CRH)
3. Increased sympa tone, increase in basal metabolic rate
4. Decrease in insulin secretion from pancreas

e.g. zucker rats have a mutation in the leptin receptor making the animal insensitive to circulating leptin

so why do people become resistant to leptin?
- Leptin and its receptor (severl of them) first isolated in 1990s and at the time believed that leptin may prove to be a great weight-loss drug
- clinical trials were disappointing: heavy people have plenty of leptin, they seem to grow resistant to its effects

Body Mass Index Def'n & Table

- with metric system, formula for BMI is = weight in kilograms / height in meters squared
- height usu measured in cm, so divide height in cm by 100 to get height in meters
- formula: weight (kg) / (height(m))^2
- calculate BMI by dividing weight in pounds by height in inches (in) squared and multiplying by a conversion factor of 703
- however BMI is a flawed instrument
- doesn't distinguish btwn fat and muscle, so all weight is same
- individual who bulks up will be heavier but will not be fat
- also it is based on idea that there is an ideal weight for a given height
- commonly criticized as flawed logic
- useful as gross measuring device

Obesity

body mass index (BMI) of 30 or higher

BMI

measure of an adult's weight in relation to his/her height, specifically the adult's weight in kgs divided by the square of his/her height in meters

Obesity Trends Among U.S. Adults Btwn 1985-2010 (Map Data)

- In 1990, among states participating in the Behavioral Risk Factor Surveillance System, 10 states had a prevalence of obesity less than 10% and no state had prevalence equal to or greater than 15%
- By 2000, no state had a prevalence of obesity less than 10%, 23 states had a prevalence between 20-24%, and no state had prevalence equal to or greater than 25%
- In 2010, no state had a prevalence of obesity less than 20%. Thirty-six states had a prevalence equal to or greater than 25%; 12 of these states (Alabama, Arkansas, Kentucky, Louisiana, Michigan, Mississippi, Missouri, Oklahoma, South Carolina, Tennessee, Texas, and West Virginia) had a prevalence equal to or greater than 30%.

Why are these map trends happening? (five possible reasons)

Phenomena is very poorly understood and is spreading throughout the world as more countries adopt Western diets and lifestyles

- sedentary lifestyle
- abnormal feeding
- social and psychological factors
- childhood overeating
- physiological factors

- 3 images (graphs/tables) showing obesity trends mirroring diabetes trends; more CDC data looking at childhood obesity trends
- Childhood obesity is widely regarded as leading to multiple lifelong health problems

1. Sedentary Lifestyle

- modern urban life frequently does not include physical exertion
- Regular exercise not only increases muscle mass and reduce fat, but increases basal metabolic rate
- AHA and sports medicine recommend: 30 min mod-intensity activity 5 days a week, or at least 20 min vigorous aerobic activity (running) three days a week, plus strength training exercises twice a week

2. Abnormal Feeding

modern processed foods are frequently cited as contributing to the obesity epidemic

3. Social and Psychological Factors

- studies show that being around thinner people tends to make people loose weight, while being around heavier people tends to encourage weight gain
- Advertizing encourages consumption, often replacing 'healthy' foods with less healthy ones; candy snacks instead of fruit

4. Childhood Overeating

lifestyle is largely taught to children, it is argued that American (and generally Westerners) taught to overeat, three filling meals a day

5. Physiological Factors

in a minority of cases there are mutations in E regulation system which result in obesity, mutations in MCR-4 or lack of leptin receptors

Treatment for Obesity (drugs & two surgery options)

- to loose weight, either have to burn more E, ingest less E, or ideally do both
- NIH guidelines recommend decreasing Caloric intake by 500 Calories (500 kilocalories) per day to loose 1lb/week for people with BMI btwn 25-35
- Over 35: NIH recommend sdropping 500-1000 Calories per day to loose 1-2 pounds per week, or 10% body weight over 6 months

Drugs:
- various drugs used, most widely are amphetamines which inhibit feeding centers and increase E expenditure (suppress appetite while increasing metabolic rate)
- Side effects include dependency, elevated bp and other cardiovasculature problems, nervousness, irritability
- Other drugs inhibit lipase, interfere with lipid digestion
- Side effects are fecal fat loss

Surgery:
1. gastric bypass
2. gastric banding

Gastric Bypass Surgery

- upper part of stomach connected to jejunum
- Al Roker: had gastric bypass surgery

Gastric Banding Surgery

surgery where band placed around stomach

Vitamins (seven of them)

1. Vitamin A
2. Thiamine B1
3. Niacin (nicotinic acid)
4. Riboflavin B12
5. Folic Acid
6. Pyridoxine B6
7. Ascorbic Acid C

1. Vitamin A

- in animal tissues as retinol, as provitamin in plants, esp yellow vegetables (carotenoid pigmentys)
- it is needed for formation of retinal pigments, night vision

2. Thiamine B1

- cocarboxylase, works with decarboxylases in multiple reactions (e.g. krebs cycle) to split CO2 from substrate
- deficiency known as beriberi: shifts E utilization away from proteins and towards fats, causes breakdown of myelin, weakened cardiac muscle, vasodilation and edema

3. Niacin (nicotinic acid)

- functions as coenzyme as H+ acceptor during digestion
- deficiency provokes muscle weakness, skin lesions, inflammation of GI systems, CNS effects (dementia)

4. Riboflavin B12

- H+ carrier in mitochondrial rxns
- B12 needed in gene replication
- Deficiency effects similar to niacin, loss of oxidative activity

5. Folic Acid

- Fxns as coenzyme in formation of AAs
- Deficiency related to poor growth, birth defects

6. Pyridoxine B6

- Functions as coenzyme in formation of AAs
- Deficiency results in anemia, poor growth

7. Ascorbic Acid C

- Essential in activating enzymes involved in collagen formation
- Deficiency results in scurvy
- Fragile blood vessels, bone-growth failure, widespread lesions, failure to heal

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