Integration of Metabolism: Organ Systems and Dyslipidemia

Brain

• No energy storage

• Prefers glucose or keton during fasting

• No export

Adipose

• Stores TAG

• Uses Glycose, glycerol and Fas

• Exports free FAs and glycerol

Liver

• Stores glycogen and some TAG

• Uses glucose, alanine, lactate, FAs and glycerol

• Exports glucose, ketone bodies, VLDL-TAG

Heart

• Stores minimal glycogen

• Primarily uses FAs, lactate ,ketones and glucose

• Doesn't export

Skeletal muscles

• Stores glycogen, some TAG, protein

• Uses glucose, FAs, ketones

• Exports Lactate and alanine

Intestine

• Stores minimal, transient TAG

• Uses glucose and glutamine

• Exports chylomicrons and glucose

Anatomy and structure of the liver

Physiological integration

• Hub of nutrient processing, buffering dietary inputs and redistributing fuels to other organs

Anatomy and structure

• Largest internal organ (2-4% weight), receives dual blood supply (75% from hepatic portal vein, carries nutrient-rich venous blood from intestine and 25% from hepatic artery providing oxygenated blood)

• Blood flows through lobules, liver's functional units, hepatocytes are arranged in plates radiating from a central vein

• Between plates are sinusoids, fenestrated vascular channels that permit extensive exchange between blood and hepatocytes and contains resident macrophages (Kupffer cells)

• Opposite side of each hepatocyte are tiny bile canaliculi which collect secreted bile, drains into bile ductules, into larger bile ducts that carry it to the gallbladder for storage

Adipose: Beyond fuel storage - endocrine hub

• Secrete hormones into bloodstream, allows messengers to act on distant cells or organs to regulate metabolism, growth and homeostasis

• Function as energy reservoir and endocrine organ

  • Stores TAG and release FFA and glycerol during fasting to fuel liver muscle and heart

• Also Secrete adipokines/cytokines that regulate systemic metabolism:

  • Leptin = signal satiety to hypothalamus, regulate intake/energy expenditure

  • Adiponectin: enhance insulin sensitivity in liver/muscles and promote FA oxidation

  • Restine/TNF-alpha: modulate inflammation and reduce insulin sensitivity

  • IL-6 and other cytokines: influence hepatic glucose production and systemic inflammatory response

Small Intestine: Absorption and Hormones

• Duodenum: Nutrient sensing and initial digesoin

  • Chyme, bile acids and pancreatic enzymes drive rapid breakdown of carbs, proteins and lipids

  • Enterocytes fueled with glucose and glutamine and maintain minimal internal energy reserves

  • Releases hormones (CCK and secretin) to orchestrate gallbladder contraction, pancreatic enzyme output, luminal pH control

• Jejunum: Primary Absorptive Engine

  • Absorbs most sugars, amino acids, peptides and lipids by high capacity transporters SGLT1

  • Enterocytes use glutamine as a major fuel to support rapid mucosal turnover

• Ileum: Bile Acid recycling and Incretin signaling

  • Absorbs bile acids and vitamin B12

  • Drives enterohepatic circulation

  • L-cells senses luminal nutrients + release hormones like GLP-1, drives insulin secretion, slows gastric emptying and suppressing appetite

  • Enterocytes rely on FAs and glutamine

• Small intestine links nutrient absorption to whole-body metabolic control

  • Using glutamine and FAs for energy

  • Secrete hormones to coordinate, hepatic metabolism, glucose homeostasis, satiety and overall post-meal physiology

GLP-1 receptor agonism: Ozempic's metabolic effects

Incretin Hormone and semaglutide

• GLP-1 is an ilium secreted gut hormone that boosts glucose-dependent insulin secretion. Semaglutide (Ozempic) is a long-acting synthesis GLP-1 receptor agnost that mimics the effect

 

Semaglutide

• Binds to GLP-1 receptors on pancreatic beta and alpha cells, hypothalamic neurons and the gut

• Activates signaling to exchange glucose-dependent insulin, suppress glucagon, slow gastric emptying and reduce appetite

• Reduces appetite by activating receptors in hypothalamus and brainstem to promote satiety

• Signals from gut and vagal GLP-1 receptors and slow gastric emptying reduces food intake and prolong fullness

• 1 weekly dose profile

• Improve glycemic control, promote weight loss and offer cardiovascular benefits in type 2 diabetes

Muscle in Motion: Skeletal, smooth and cardiac

Skeletal

• Striated and multinucleated

• Organized to sarcomeres

• Voluntary control

• Metabolically they have a high capacity for glycolysis and Oxphos, storing glycogen and oxidizing FAs to meet energy demand

Smooth Muscle

• Non-straited, spindle shaped cells with 1 nucleus, no striation

• Involuntary contraction

• Use oxidative metabolism of FAs and Glucose

• Lines hollow organs like gut, blood vessels and bladder

• Regulate peristalsis, vessel tone and organ filling

Cardiac Muscle

• Striated and branched with 1 central nucleus, connected by disc to allow synchronize contraction

• Highly oxidative rely of Fas and glucose with abundant mitochondria (40% of cell) to sustain continuous rhythmic contraction

• Involuntary contraction, tightly regulated by endocrine and autonomic signals

• Contracts continuously

ATP on demand: How muscles powers and recovers

Muscle energy metabolism

• Myocytes are specialized ATP generators, relies on glycogen, and circulating Glucose and FAs

• Glycogen provides rapid internal glucose source

• Skeletal muscles lack glucose 6-phasphatase so Glucose is metabolized locally for contraction

Anaerobic Glycolysis

• During intense activity, glycolysis outpaces TCA

• Pyruvate is converted to lactate and sustains ATP production when O2 is limiting

• Lactate is exported for system use than feed TCA locally

Post-Exercise Oxygen Uptake

• After exercise, elevated O2 consumption fuels Ox Phos and drives the Cori cycle in the liver converts lactate back to glucose and replenishes glycogen

Brain

Glucose metabolism

• Neurons rely on glc exclusively, normal levels is around 70-100mg/dL

• Below 45 compromises function

• Ketone bodies become major neuronal fuel during glucose scarcity like starvation, neonatal development and ketogenic diets

PET imaging of Brain glucose utilization

• Fluorodeoxyglucose (FDG), a Glc analog, is injected into the bloodstream and taken up by active neurons

• After phosphating by hexokinase, FDG becomes trapped, allows PET scnas to visualize regional metabolic acitivty across the brain

Effects on Rest/Sleep deprivation

• Well rested individuals have uniform and high glucose uptake, optimal neuronal activity

• 48 hours of sleep deprivation, reduces glucose uptake, impaired neuronal function

Brain energy metabolism: Powering Neuronal function

Energy metabolism

• Has minimal fuel reserves, consumes 120 Glc per day, 25% of resting humans total energy

Major Energy uses

• Most energy 70-80% power N*/K* ATPase, maintains membrane potentials for AP and synaptic transmission

• Additional ATP supports NT synthesis, vesicle recycling and receptor maintenance, enable rapid/precise neuronal communication

Energy production and coupling

• Neurons generate ATP by OxPhos with glycolysis contributing under high demand or low oxygen

• Lactate can act as a shuttle fuel between astrocytes and neurons

• Brain metabolism is linked to blood flow and nutrient availability

• Brief glucose drops can impair function

Kidney: filtration, acid handling and Glucose production

Anatomy and function

• Receives blood through renal artery, delivers plasma to million of nephrons

• Glomerulus perform filtration, generates initial filtrate while proximal tubule, loop of Henle, distal tubule and collecting duct fine-tune solute and water balance

• Filtered blood exists by the renal vein and waste leaves in urine

Core metabolic role

• Filters plasma to excrete urea, creatine and excess ions

• Selectively reabsorbs Glc, amino acids, bicarbonate and electrolytes

• Major controller of systemic pH, reclaiming bicarbonate and secreted proteins to maintain acid-base balance

Renal gluconeogenesis in starvation

• During faster, kidney becomes a major gluconeogenic organ, contributes to 40% of endogenous Glucose

• Glutamine is preferred gluconeogenic precursors

Ammonia production and Acid handling

• Surge in ketone body-derived acidity during stavation triggers increase glutamine catabolism

• Each glutamine creates 2NH3 and buffers H+ in the tubular lumen as NH4+

• Resulting in alpha ketoglutarate is diverted into gluconeogenesis

• This removes acid and generates glucose

 

Liver controls nutrient distribution and adapts enzyme rapidly (5-10x faster turnover)

• Carb metabolism

  • Glycogen storage/metabolism and gluconeogenesis to maintain blood glc during fasting

• Lipid metabolism

  • De novo FA synthesis, FA B-oxidation, TAG production, VLDL export, Ketone bodies generation

• Cholesterol and Bile Acid Metabolism

  • Synthesize cholesterol, remove HDL, clear LDL and produce bile acids for lipid digestion

• Protein and nitrogen metabolism

  • Catabolize amino acids, detoxifies nitrogen via urea cycle, synthesize plasma protein including albumin

• Detoxification and biotransformation

  • Metabolizes drugs, hormones and toxins by cytochrome P450 enzymes and detoxifies ammonia and other waste

Liver is rapidly adapting to nutrient availability

• Enzyme turns over 5-10X faster than those in other tissue, allows hepatocytes to shift priorities Swithing after

After protein-meal

• Upregulate amino acid catabolism including the urea cycle and enzymes for gluconeogenesis to manage excess nitrogen and maintain glucose homeostasis

• Upregulated enzymes: Alanine aminotransferase, glutamate dehydrogenase, PEPCK, glucose-6-phosphatase

After a carbohydrate-rich meal

• Hours after protein-catabolizing enzyme decreases, enzymes for glycolysis, glycogen synthesis and FA synthesis rises, prepares liver to store and redistribute energy efficiently

• Upregulated enzymes: glucokinase, pyruvate kinase, glycogen synthase, ACC, FAS

Connection between Liver and Adipose tissue: TAG cycle, dynamic lipid flow for metabolic flexibility

• Undergo continuous breakdown and resynthesis cycle across adipose tissue, liver and muscle

• During lipolysis in adipocytes, FAs are release

  • Some enter circulation to fuel oxidation tissues like muscles

  • Others re-esterified back into TAGs in adipocytes

• Circulating FAs are taken up by the liver, incorporated into TAGs and exported in VLDL Return to adipose for storage

• Cycle maintains a readily mobilizable lipid pool in the bloodstream for acute energy demands

  • Enables rapid adaptation to fluctuating nutrient states or flight/fight scenarios

  • Contribute to metabolic flexibility by allowing FAs to continuously redistributed between adipose storage and tissue that burn them for energy like muscle, heart and liver even during fasting

• TAG cycle isn't futile - ensures energy availability, metabolic flexibility and rapid lipid mobilization across tissues

Fatty liver disease

• Excess TAGs in hepatocytes form imbalance lipid metabolism

• Non-alcoholic FLD, insulin resistance drives de novo FA synthesis, beta-oxidation and VLDL export lags

• Alcoholic FLD, ethanol metabolism produces NADH, inhibiting fat oxidation and promotes TAG storage

• Chronic FLD can progress to steatohepatitis, fibrosis and cirrhosis, impairs carbohydrate/lipid/a.a metabolism

Obstructive Liver Disease (Cholestasis)

• Blocked bile flow, prevents liver form exporting bile acids and cholesterol and lipid-soluble nutrient

• It disrupts intestinal lipid digestion and hepatocyte metabolism

• Bile acid accumulation alters enzyme regulation, suppresses bile acid synthesis and triggers detoxification pathways

• Chronic obstruction impairs the liver's metabolic output and nutrient distribution

Malignant Liver Disease

• Primary or metastatic tumor reprogram hepatocyte metabolism, increases glycolysis and glutamine use for tumor growth

• Normal liver functions like gluconeogenesis, glycogen storage, lipid synthesis and urea production are compromised

• Hijacking causes systemic energy imbalances, dyslipidemia and impaired detoxification

Metabolic priorities in starvation

• First priority is to supply glucose to the brain and RBC

• Early on it comes from liver glycogen, as fasting continues energy shifts to FAs and ketone bodies to spare muscle protein while maintaining organ function

Fuel reserves, 3 main sources

• Liver and muscles glycogen for quick Glc

• TAGs in adipose is the largest reserve

• Muscle protein as a last resort fo gluconeogenesis

 Starvation

Early Starvation

• After last meal, blood glucose drops and glucagon rises

• Drives glycogen breakdown and gluconeogenesis to maintain glucose for tissue

Later adaptation

• When glycogen is depleted, lipolysis ramps up, provides Fas to peripheral tissues

• Converts FAs into ketone bodies which the brain gradually uses, reducing Glc demand

• Kidneys increase glutamine gluconeogenesis

• Minimal muscle protein breakdown continues to supply some amino acids for gluconeogenesis

Multi organ Response

• Brain/heart adapts to ketones

• Peripheral tissues rely on fat

• Liver orchestrates glucose and ketone supply

• Characterize the liver's anatomical architecture in relation to its diverse metabolic

and detoxification functions.

• Largest internal organ (2-4% weight), receives dual blood supply (75% from hepatic portal vein, carries nutrient-rich venous blood from intestine and 25% from hepatic artery providing oxygenated blood)

• Blood flows through lobules, liver's functional units, hepatocytes are arranged in plates radiating from a central vein

• Between plates are sinusoids, fenestrated vascular channels that permit extensive exchange between blood and hepatocytes and contains resident macrophages (Kupffer cells)

• Opposite side of each hepatocyte are tiny bile canaliculi which collect secreted bile, drains into bile ductules, into larger bile ducts that carry it to the gallbladder for storage

Dyslipidemia: Lipid imbalance and cardiometabolic risk

• Metabolic disorder by disrupted circulating lipid and lipoprotein levels

  • Includes TAGs, cholesterol, phospholipids, free FAs and major lipoprotein classes

• Abnormalities impair lipid transport and metabolic signaling, driving atherogenesis and cardiometabolic dysfunction

Clinical importance: major risk factor for atherosclerotic cardiovascular disease

• Includes:

  • Coronary artery disease (heart attack, angina)

  • Cerebrovascular disease (stroke, transient ischemic attack

  • Peripheral artery disease (limb ischemia)

• Causes

  • Primary (genetic): familial hypocholesterolemia (LDL, receptor defect)

  • Secondary (acquired): obesity, type 2 diabetes, excess dietary fats, sedentary lifestyle, chronic kidney or liver disease

Cholesterol is found in LDL derived from VLDL

• Liver exports VLDL particle with both TAG and cholesterol

• Lipoprotein lipase in capillaries remove TAG from VLDL

• As TAG is lost praticles become

  • Smaller in radius

  • Denser

  • Relatively enriched in cholesterol

• VLDL > LDL

  • Particles are small enough to deliver cholesterol to peripheral tissues by receptor-mediated endocytosis

  • High levels of LDL are strongly correlated with atherosclerosis and heart disease

 

Lipid metabolism and insulin resistance

• Obesity = excess adipose tissue

• Obese individuals are metabolically health with normal whole body insulin sensitivity but it is a major risk for developing insulin resistance

Diabete dyslipidemia in Type 2 diabetes

• Insulin resistance alters lipid metabolism

  • Increase VLDL secretion by the liver due to increase FFA flux from adipose tissue

  • Increase LDL levels, partily from impaire clearance

Paradox: insulin normally stimulates VLDL production

• But in insulin resistance , lipolysis in adipose is not suppressed

• More FFAs delivers to liver, drives VLDL overproduction

• Insulin signaling promotes lipoprotein clearance is impaired

Paradox resolves Why VLDL remains high in insulin resistance

1. Adipose dysfunction due to insulin resistance leads to excess release of FFAs into circulation

2. Liver uptake FFAs >increase TAG synthesis > increase VLDL secretion (liver retain capacity in insulin resistance)

3. Muscle and liver lipid overload

   1. Lipid accumulation, DAGs and ceramides activate stress and inflammatory pathways that block insulin receptor signaling

   2. Leads to local insulin resistance causing impaired muscle glucose uptake and failure to suppress hepatic glucose

Lifestyle changes to reverse resistance

• Exercise and eat less saturated FA

• High dietary saturated fat is strongly associated with high total cholesterol, high LDL and heart disease risk

• Unsaturated fat (not trans but naturally occurring cis) decrease LDL compared to saturated fat

• Monosaturated fat are favorable compared to polyunsaturated fat

• Sensitivity to slight geometric difference suggests a beneficial signaling role of unsaturated FA or detrimental signal role of saturated FA