Lesson 77: Liver Functions

The liver is the largest internal gland and one of the most metabolically active organs in the body. It occupies a central position in the regulation of:

energy metabolism, nutrient processing, synthesis of plasma proteins, lipid and cholesterol and AA and bilirubin metabolism

nitrogen disposal

vitamin and mineral homeostasis, and biotransformation of endogenous and exogenous compounds

Major functions of the liver: carb metabolism

Glycogenesis, Glycogenolysis, Gluconeogenesis, Glycolysis

Regulation of blood glucose

Major functions of the liver: lipid metabolism

Fatty acid oxidation

Fatty acid, TG, cholesterol, lipoprotein synthesis

Cholesterol elimination

Ketogenesis

Major functions of the liver: protein and AA metabolism

Amino acid uptake

Transamination, Deamination

Urea and Plasma protein synthesis

Acute-phase protein production

Major functions of the liver: bilirubin metabolism

Uptake, Conjugation, Excretion

Major functions of the liver: vitamin metabolism

Storage, Activation, Metabolism, Transport

Major functions of the liver: mineral metabolism

Iron, Copper, Zinc

Major functions of the liver: biotransformation

Phase I reactions

Phase II reactions

Phase III transport/excretion

Major function of the liver: Endocrine and hormonal metabolism

Metabolizes hormones

Produces hormone-binding proteins

Participates in IGF-1 production

Converts or regulates several biologically active compounds

Functional organization of the liver: functional unit is the Hepatic lobule

Blood enters it from branches of the portal vein and hepatic artery and flows through sinusoids toward the central vein

bile flows in the opposite direction through bile canaliculi toward the portal triads

Liver blood supply: Hepatic portal vein(Supplies approximately 70–75% of hepatic bloodflow)

carries glucose, amino acids, fatty acids, nutrients, gut-derived metabolites, microbial products, some toxins, and drugs absorbed from the GIT

Liver blood supply: Hepatic artery provides approximately

25–30% of blood flow but contributes a substantial proportion of the liver's oxygen supply

Hepatocytes perform most of the metabolic functions: They contain abundant

Mitochondria, smooth ER, rough ER, peroxisomes, lysosomes, and Golgi apparatus

This organelle-rich structure reflects the extensive metabolic work performed by the hepatocytes

Zone 1 – Periportal

Closest to the portal triad

Receives relatively oxygen-rich blood

What is zone 1 important for?

Oxidative metabolism

Gluconeogenesis

Fatty-acid oxidation

Urea synthesis

Zone 2

Intermediate metabolic characteristics

Zone 3 – Centrilobular/pericentral

Closest to the central vein. Receives relatively less oxygen

vulnerable to hypoxia

What is zone 3s function?

Glycolysis

Lipogenesis

Ketogenesis

CYP450-mediated drug metabolism

Diagram of the zones

Liver absorptive phase: timeframe

Lasts roughly 4 hours after eating a meal, while nutrients pass through the gastrointestinal tract and enter the blood

Liver absorptive phase: primary hormone

Insulin spikes in response to rising blood glucose and AA levels, driving anabolism (building up stores) and nutrient uptake

Function of the absorptive phase:

Carbohydrate, Lipid, Protein Metabolism

Liver postabsorptive phase: timeframe

Begins roughly 4 hours after a meal(when gut absorption is complete) and lasts until

the next meal

Liver postabsorptive phase: primary hormone

Glucagon (along with a drop in insulin and a rise in counter-regulatory hormones like epinephrine and cortisol) signals the release of stored energy

Function of the postabsorptive phase of the liver

Carbohydrate & Glucose Pathways

Gluconeogenesis

Lipid Metabolism (Glucose-Sparing)

Glycogenesis

biological process of creating glycogen from excess glucose molecules for energy storage

occurs primarily in the liver and skeletal muscles when blood glucose is relatively high, such as after feeding

Purpose of glycogenesis

key enzyme is glycogen synthase

Keeps blood sugar stable and stores energy for future use

Glycogenesis trigger

Stimulated by the hormone insulin when blood sugar levels are high, such as after a meal

Insulin Promotes:

Glucose uptake/use, Glycogenesis, Lipogenesis

Insulin inhibits

Glycogenolysis

Gluconeogenesis

Glycogenolysis

Breakdown of glycogen into glucose-1-phosphate and glucose to provide immediate energy and maintain blood sugar levels

liver is particularly important because it can release free glucose into the circulation

A key distinction between the liver and skeletal muscle is that?

hepatocytes have glucose-6-phosphatase, which converts glucose-6-phosphate

to glucose, allowing it to enter the bloodstream

Skeletal muscle lacks sufficient glucose-6-phosphatase for this purpose and primarily uses its glycogen for its own energy needs

Hormonal regulation of glycogenolysis: Glucagon

Released by the pancreas during fasting or low blood sugar; stimulates glycogenolysis specifically in the liver to raise blood glucose

Hormonal regulation of glycogenolysis: Epinephrine (Adrenaline)

Released by the adrenal glands during stress or exercise; stimulates glycogenolysis in the liver and skeletal muscle

Hormonal regulation of glycogenolysis: Insulin

Released after a meal when blood sugar is high; it inhibits glycogenolysis and promotes glycogen storage (glycogenesis)

Liver creates new glucose from non-carbohydrate sources to keep blood sugar stable: It is particularly important during

Fasting, Prolonged exercise, Starvation, Increased metabolic demand

Major gluconeogenic substrates include:

Lactate, Glycerol, Glucogenic amino acids

Propionate in ruminants

Propionate is the major glucogenic volatile fatty acid

converted in the liver to: Propionate → Succinyl-CoA → Oxaloacetate → Glucose

Hepatic gluconeogenesis is essential for?

maintaining glucose homeostasis in ruminants

Fed state: Insulin dominates

The liver promotes: Glycogenesis, Glycolysis, Lipogenesis, Protein synthesis

Fasting state: Glucagon and other counter-regulatory hormones dominate

liver promotes: Glycogenolysis, Gluconeogenesis, Fatty-acid oxidation, Ketogenesis

Lipid metabolism: fatty acid uptake

Process by which hepatocytes absorb circulating non-esterified free fatty acids to regulate energy balance, lipid storage, and lipoprotein secretion

Fatty acids reach the liver from:

Dietary lipids, Adipose tissue, Lipoproteins, De novo synthesis

During fasting, adipose tissue releases non-esterified fatty acids into the circulation. The liver takes them up and decides whether to:

Oxidize them

Convert them into triglycerides

Incorporate them into phospholipids

Produce ketone bodies

Beta-oxidation is the mitochondrial metabolic pathway that breaks down?

fatty acid molecules two carbons at a time to generate acetyl-CoA, NADH, and FADH₂.

Each cycle removes a two-carbon unit as: Acetyl-CoA

while producing: NADH, FADH₂

NADH, FADH₂

These reducing equivalents generate ATP through oxidative phosphorylation

Fatty acid synthesis

building of fatty acids from acetyl-CoA and malonyl-CoA using NADPH to store energy and form cell membranes

Location and transport of fatty acid synthesis: Cytosol

De novo synthesis happens in the cell cytoplasm, mainly in the liver and fat tissue

Location and transport of fatty acid synthesis: Citrate Shuttle

Acetyl-CoA is made inside mitochondria but cannot cross the membrane directly

It leaves the mitochondria as citrate (bound with oxaloacetate)

Location and transport of fatty acid synthesis: Cytoplasmic Release

In the cytosol, ATP citrate lyase breaks citrate back down into acetyl-CoA and oxaloacetate

Fatty acid synthesis is primarily regulated at the rate-limiting carboxylation step catalyzed by the enzyme acetyl-CoA carboxylase (ACC)

Insulin: Stimulates lipogenesis

Glucagon: Inhibits lipogenesis and promotes mobilization/oxidation of stored energy.

An important regulatory molecule is: Malonyl-CoA

Triglyceride synthesis (lipogenesis) is

the metabolic pathway that builds triglycerides from a glycerol backbone and three activated fatty acids for energy storage.

The liver can esterify fatty acids with glycerol-derived substrates to form triglycerides.

Main Classes of Lipoproteins: Chylomicrons

The largest and least dense particles; they carry fats from the intestines into the

bloodstream or lymphatic system

Main classes of lipoproteins: VLDL (Very-Low-Density Lipoproteins)

Made by the liver to carry newly made fats to tissues

Main classes of lipoproteins: IDL (Intermediate-Density Lipoproteins)

Formed when VLDL loses some of its fat

Main classes of lipoproteins: LDL (Low-Density Lipoproteins)

Rich in cholesterol; they deliver cholesterol to cells (often called "bad" cholesterol).

Main classes of lipoproteins: HDL (High-Density Lipoproteins)

The densest particles; they bring extra cholesterol back to the liver (often called "good" cholesterol)

Lipoprotein metabolism is divided into?

Exogenous Pathway (processing dietary fats from the gut)

Endogenous Pathway(processing lipids synthesized inside the body, mainly by the liver)

Cholesterol synthesis is a multi-step biochemical pathway that builds?

a 27-carbon sterol molecule from acetyl-CoA in the cytosol and endoplasmic reticulum of mammalian cells

The rate-limiting enzyme is: HMG-CoA reductase

Bile acid synthesis: The primary pathway for the catabolism and excretion of cholesterol

Converts cholesterol into water-soluble primary bile acids(cholic acid and chenodeoxycholic acid)

essential for lipid digestion, cholesterol excretion, and systemic metabolic signaling

Enterohepatic Circulation

The recycling pathway where bile acids, bilirubin, and certain drugs travel from the liver into the bile and small intestine, get reabsorbed into the portal vein, and return to the liver

Enterohepatic circulation: Bile Acid Conservation

Bile acids are reabsorbed in the terminal ileum and returned to the liver via the portal vein

Enterohepatic circulation: Fat and Vitamin Digestion

Recycling ensures a steady, high concentration of bile salts in the duodenum to emulsify dietary fats and support the absorption of fat-soluble vitamins (A, D, E, and K)

Enterohepatic circulation: Cholesterol Homeostasis

bile acids are synthesized from cholesterol, the small fraction lost daily in feces represents the primary pathway for excreting excess cholesterol

Enterohepatic circulation: Energy Conservation

Reusing bile salts saves significant metabolic energy and synthetic resources that the hepatocytes spend on continuous de novo production

Ketogenesis

Production of ketone bodies from acetyl-CoA in the mitochondria of liver cells as an alternative fuel for the brain, skeletal muscle, and cardiac muscle during prolonged fasting

Beta-hydroxybutyrate:

The most abundant ketone body circulating in the blood

Acetoacetate

The primary ketone body formed early in the pathway

Acetone

A volatile byproduct formed by the spontaneous or enzymatic decarboxylation of acetoacetate; it is exhaled through the lungs

Physiological Triggers & Regulation of ketogenesis

Low blood glucose, fasting, starvation, prolonged exercise, or a low-carbohydrate ketogenic diet

Hormonal control of ketogenesis

Upregulated by a low insulin-to-glucagon ratio, elevated cAMP, and glucagon signaling; inhibited by insulin

Ketogenesis: liver limitations

The liver cannot utilize ketones for fuel; instead, it exports them to the brain, heart, and skeletal muscle.

Ketosis (hyperketonemia)

metabolic disorder in vet med, most frequently diagnosed in high-producing dairy cows during early lactation, as well as in pregnant sheep and goats (pregnancy toxemia)

Process of ketosis

extreme negative energy balance → animal's dietary carbohydrate intake cannot keep pace with the massive glucose demands of milk production

deficit triggers the intense mobilization of body fat reserves, inundating the liver and resulting in the excess production of toxic ketone bodies like beta-hydroxybutyrate (BHB), acetoacetate, and acetone

Protein and AA digestion and absorption

Proteins break down in the stomach via hydrochloric acid and pepsin, then in the small intestine via pancreatic enzymes and peptidases into free amino acids

Protein and AA metabolism: The Amino Acid Pool

Free amino acids come from diet, tissue protein turnover, and de novo synthesis. The body cannot store excess amino acids; they are used for synthesis, converted to glucose or fatty acids, or catabolized

Transamination:

Transfer of an amino group from an amino acid to an α-keto acid (α-ketoglutarate) via aminotransferases (ALT, AST)

form new nonessential amino acids or keto acids

Deamination

Removal of the amino group (yielding free ammonia/ammonium) in the liver via glutamate dehydrogenase

The Urea Cycle

Toxic ammonia is converted into non-toxic urea in the liver through the five-step urea cycle and excreted by the kidneys in urine

Protein and AA metabolism: Glucogenic Amino Acids

Converted to pyruvate or citric acid cycle intermediates(like oxaloacetate) to fuel gluconeogenesis

Protein and AA metabolism: Ketogenic Amino Acids

Converted to acetyl-CoA or acetoacetyl-CoA (such as leucine and lysine) to produce ketone bodies or fatty acids

Liver specific functions: protein synthesis

Liver specific functions: Hormones

Liver specific functions: carb synthesis

Liver specific functions: Lipid synthesis

Liver specific functions: biotransformation and detoxification

Liver specific functions: storage