Integration of Metabolism and Hormone Action Metabolic process in single cells Whole organism Hormonal signals integrate and coordinate the metabolic activities of different tissues and bring about optimal ALLOCATION of fuels and precursors to each organ. Our focus: – The specialized metabolism of major organs – Some tissues are energy suppliers, others are energy consumers, and some are both.Question: How do these tissues communicate to each other? » Answer: Hormones.
Metabolism has highlyinterconnected pathways Central themes: – ATP is universal currency of energy – ATP is made by the oxidation of Glc, fa’s and aa’s • The common intermediate is AcetylCoA – NADPH is the major electron donor in reductive biosynthesis – Biomolecules are made from building blocks. – Biosynthetic and degradative pathways are almost always distinct! • They could be easily controlled • They become thermodynamically favorable at all times
Recurring motifs in regulation1. Allosteric interaction2. Covalent modification3. Adjustment of enzyme levels4. Compartmentation5. Metabolic specializations of organs
Major metabolic pathways and control sites1. Glycolysis PFK is the most important control point In the liver, the most important regulator is F-2,6 BP. – When blood Glc goes down, a glucagon-triggered cascade leads to the activation of the phosphatase and the inhibition of the kinase in the liver. • F-2,6BiP decreases • PFK decreases Glycolysis slows down
Major metabolic pathways and control sites2. TCA cycle and Oxidative Phosphorylation Takes place inside mitochondria The rate of the TCA cycle matches the need for ATP. – High ATP levels decrease the activities of 2 enzymes: • Isocitrate dehydrogenase • α-ketoglutarate dehydrogenase
Major metabolic pathways and control sites3. Pyruvate dehydrogenase complex Takes place inside mitochondria
Major metabolic pathwaysand control sites4. Pentose phosphate pathway Takes place in the cytosol in two stages: – Oxidative decarboxylation of G-6-Phosphate – Nonoxidative, reversible metabolism of 5C phosphosugars into phospharylated 3C and 6C glycolitic intermediates
Major metabolic pathwaysand control sites5. Gluconeogenesis Glc can be made by the liver from noncarbohydrates The major entry point of this pathway is pyruvate, which is carboxylated to OAA in mitochondria. Gloconeogenesis and glycolysis are usually reciprocally regulated so one pathway is minimally active while the other one is highly active. – If F-2,6BiP increases, gluconeogenesis is inhibited and glycolysis is activated.
Major metabolic pathwaysand control sites6. Glycogen synthesis and degradation Glycogen synthesis and degradation are coordinately controlled by a hormone-triggered cascade so there is no misunderstanding Enzymes to remember: – Phosphorylase – Glycogen synthase
Major metabolic pathways and control sites7. Fa synthesis and degradation Fa’s are made in the cytosol – 2C units are added to a growing chain on an acyl carrier protein. • Acetyl groups are carried from mitochondria to the cytosol as CITRATE • Citrate increases the activity of acetyl CoA carboxylase which increases fa synthesis – Malonyl CoA is formed by the carboxylation of acetyl CoA. Beta oxidation is in mitochondria – Acylcarnitine formation is important – ATP need is important – If there is too much malonyl CoA, fa degradation is inhibited.
Key junctions There are 3 metabolic junctions – Glc-6-P – Pyruvate – AcetylCoA
Each organ has a unique metabolic profile Brain Muscle Adipose tissue The kidney Liver
Brain Glc is virtually the sole fuel for the human brain, except during prolonged starvation It consumes 120 g glc per day No glycogen strores in the brain During prolonged starvation, acetaacetate is used Fas do not serve as fuel in the brain because – They are bound to albumin in plasma; therefore, they cannot pass the blood brain barrier. – In essence, ketone bodies are transported equivalents of fa’s
Muscle Muscle differs from brain in that muscle has a large store of glycogen – 75% of glycogen is in muscle. – The energy consumption increases with muscle activity – CORI cycle • In actively contracting skeletal muscle, the rate of glycolysis far exceeds that of the citric acid cycle, and much of the pyruvate formed is reduced to lactate. • Lactate goes to liver and is converted to glc again
Heart muscle For reasons that are not clear, the heart relies mainly on fatty acids. – One possibility is that fatty acid supply is more reliable than the fluctuating carbohydrate supply. – Most organisms have a very extensive supply of fa’s; thus the functioning of the heart muscle is protected
Adipose tissue The TAGs are stored here. – They are enormous reservoir of fuel. Adipose cells need glucose for the synthesis of TAGs The glucose level inside adipose cells is a major factor in determining whether fatty acids are released into the blood. – If too much food, then FFA is stored. – If Glc and glycogen are NOT enough, then TAG is converted to FFA with the excess re-esterified in the liver to form TAG.
The kidney Major role: to make urine – The blood plasma is filtered nearly 60 times each day in the renal tubules. During starvation, the kidney becomes an important site of gluconeogenesis and may contribute as much as half of the blood glucose!
Liver The liver serves as the body’s distribution center, detoxification center, and central clearing house. – Metabolic hub – The liver plays an essential role in the integration of metabolism. Liver removes 2/3 of the glucose from the blood. – The absorbed Glc is converted into G-6-P. – G-6-P has many fates • Fa, cholesterol, or bile synthesis • Glycogen synthesis • PPP
liver When fuels are increased, fa’s are derived from the diet or synthesized by the liver as TAGs – They are secreted into the blood in the form of VLDL During fasting, the liver converts fa’s into ketone bodies The liver also plays an essential role in amino acid metabolism – It secretes 20-30 g urea/day Liver meets its own energy by using α-ketoacids.
Food intake and starvationinduce metabolic changesStarved-fed cycle Nightly starved-fed cycle has 3 stages: • Postabsorbtive state • Early fasting during the night • The refed state after breakfast Main goal is to maintain glc homeostasis!
Food intake and starvationinduce metabolic changesThe well-fed state After the consumption – Glc, aa’s and lipids are transported to the blood. – The secretion of insulin increases. – Insulin increases the uptake of Glc into the liver by GLUT2 – Insulin also increases the uptake of Glc by muscle and adipose tissue
Early fasting state The blood Glc decreases several hours after a meal – Insulin decreases – Glucagon increases • Glucagon signals the starved state • It mobilizes the glycogen by cAMP pathway • The main target organ of glucagon is the liver. – Net result: Increase glucose in blood
The refed state Fat process same as fed state The liver does not initially absorb glc from the blood, but rather leaves it for the peripheral tissues Liver stays in gluconeogenic mode Newly made Glc is used to make glycogen As blood Glc increases, the liver completes the replenishment of its glycogen stores
Metabolic adaptation in prolonged starvationminimize protein degradationWhat are the adaptations if fasting is prolongedto the point of starvation? – 70 kg man has fuel reserve ~ 161,000 kcal – The energy need for a 24 hr cycle is 1600-6000 kcal – So, fuels are ok for 1-3 months! The very first priority of metabolism in starvation – Providing Glc to the brain and other tissues The second priority of metabolism in starvation is to preserve protein, which is accomplished by shifting from glc to fa’s
After 3 days of starvation Liver forms keton bodies Their synthesis from AcetylCoA is increased because TCA is not running(gluconeogenesis depletes the supply of oxaloacetate) So, liver makes lots of KBs The brain begins to use acetoacetate After 3 days, 1/3 of the energy comes from KBs for the brain The heart also uses KBs
Obesity It is an epidemic. – Nearly 30% of the adults are obese in the US. It is a risk factor for – Diabetes – Hypertension – Cardiovascular diseases Cause is simple: – More food taken than needed Two important signal molecules: – Insulin – Leptin
Diabetes Incidence: 5% of the population Most common metabolic disorder Type I – Insulin-Dependent Diabetes Mellitus – IDDM – No insulin formed – The diabetic person is in biochemical starvation mode despite a high concentration of blood glucose. Because insulin deficient, and the entry of glucose into adipose and muscle cells is impaired. Type II – Non-Insulin-Dependent Diabetes Mellitus – NIDDM – Accounts for more than 90% of the diabetes cases – Insulin production is normal or higher than normal.
Metabolic changes during exercise Sprinting and marathon running are powered by different fuels to maximize power output – A 100 meter sprinter uses: • Stored ATP • CP • Anaerobic glycolysis of muscle glycogen – A 1000 meter runner • Oxidative phosphorylation starts. – Marathon requires a different selection of fuels • A nice cooperation between muscle, liver, and adipose tissue • Total glycogen stores (103 mol of ATP) are insufficient to provide 150 mol of ATP. • Fat breakdown is needed.
Ethanol alters energy metabolism in the liver EtOH causes many health problems Liver damage takes place in 3 stages – Fatty liver – Alcoholic hepatitis – Cirrhosis (fibrous structure and scar tissue around dead cells)