Liver physiology 5: Hepatic metabolism of lipids Flashcards
What does the liver do?
o Detoxification: Filters & cleans blood of waste products (drugs, hormones)
o Immune functions: Fights infections and diseases (RE system)
o Involved in Synthesis of clotting factors, proteins, enzymes, glycogen and fats
o Production of bile & breakdown of bilirubin
o Energy storage (glycogen and fats)
o Regulation of fat metabolism
o Ability to regenerate
Metabolic role of the liver
• The liver maintains a continuous supply of energy for the body by controlling the metabolism of CHO and fats.
• Its role varies during:
– Fasting, absorption, digestion & metabolism
– Multiple pathways
• The liver is regulated by:
– Endocrine glands eg pancreas, adrenal, thyroid
– Nerves
Tri(acyl)glycerides (TG, TAG)
1 glycerol molecule esterified to 3 fatty acids (bonded at carboxyl head) Storage form of fat in our body • Adipocytes • Hepatocytes • Elsewhere
lipid functions
• Energy reserve
• Structural and other functions
– Part of cell membranes
– Integral to form and functions of cells
– Inflammatory cascades (LC-PUFAs precursors to eicosanoids e.g. prostaglandins)
• Hormone metabolism
– Cholesterol is backbone of adrenocorticoid and sex hormones
– Vitamin D
Energy and lipids
• Almost all energy required is provided through oxidation of lipids & carbohydrates (& proteins)
• Lipids yield 9-10 kcal energy per gram
• Energy reserves
– Blood glucose 40kcal = a few minutes
– Glycogen stores 600 kcal = a day
– Muscle (protein) 25000 kcal = 7-10 days
– Lipid reserve 100000 kcal = 30 – 40 days
• Liver is main storage place for glycogen
Lipid transport – general points
- Lipids are often transported as TGs or FAs bound to Albumin or within lipoproteins
- TGs cannot diffuse through cell membrane
- FA are released through lipases to facilitate transport into the cells
- In the cell FA are re-esterified to TG
Fatty acid uptake
• Diffusion through the lipid bilayer of the cell membrane
• Facilitated transport
– Increases if increased substrate (↑supply) or increase in receptor molecules (↑ demand)
– Several transporter systems
• FA binding protein (= mitochondrial AST)
(induction to increased expression may result in increased uptake of FA in the hepatocytes)
• FAT - fatty acid translocase
• FATP - FA transport polypeptide
Insulin action and lipid metabolism
Insulin:
• Fat storage in adipocyte
• Stimulates LPL → breakdown of TG, release FFA to store (in the form of TG) in adipocytes
• Reduces activity of HSL (hormone sensitive lipase) leading to reduced FA export from adipocytes
Insulin resistance:
• Increased lipolysis in adipocytes leading to increased TG in circulation
• Increased “offer” of FA to hepatocytes leading to increased uptake
• Increased glucose level leads to less demand for lipids to be used as energy source
De novo lipogenesis in the liver 1
• Dependent on insulin concentration and sensitivity
• Hepatic de novo lipogenesis primarily is for export in lipoproteins:
– Energy source
– Structural components for membranes
• Sequential extension of an alkanoic chain starting from Acetyl-CoA via serial decarboxylative condensation reactions
• Rate limiting step: Acety-CoA to Malonyl-CoA catalysed by Acetyl-CoA carboxylase
• Rate is also related to FAS – FA synthetase
– Humans expression in Liver»_space; adipose tissue
– Activated by Insulin, substrate (citrate, isocitrate)
– Inactivated by catecholamines, glucagon
– Negative feedback – high FAS in hepatocyte inhibit FAS
Lipoproteins
• Lipoproteins consists of a core
containing TGs and cholesterol-esters and
a surface monolayer of phospholipids, cholesterol and specific protein (e.g. Apoproteins)
• Protein to lipid ratio varies
• Defined by their density (LDL, HDL, chylomicrons)
• Chylomicrons carry lipids from the gut to muscle and adipose tissue
• Chylomicron remnants taken up by the liver via receptor mediated endocytosis
Cholesterol
• Cholesterol is esterified intracellular by acyl-CoA:cholesterol acyltransferase or by lecithin: cholesterol acyltransferase in lipoproteins
• The liver is the major organ in which cholesterol is processed
• 90 % of Cholesterol is endogenous
• Excretion of cholesterol through bile is the only export system of cholesterol
• (enterophepatic circulation)
• Lipoproteins carry TG
and cholesterol through
the circulatory system
fatty acid export from the liver
- Apoprotein B (ApoB) 100 is synthesised in the rough endoplasmatic reticulum (rER)
- Lipid components (TG, Cholesterolester) are synthesised in the smooth ER (sER)
- These are added by microsomal TAG transfer protein to ApoB
- Transported in vesicle to the Golgi apparatus (GA) where ApoB is glycosylated
- Glycosylated Apo’s with lipid components buds off the GA and migrate the sinusoidal membrane of the hepatocyte
- Vesicles fuse with the membranes and VLDL is released
Oxidation
• FA oxidation is proportional plasma levels of FFA released from adipocytes • Peripheral FA mobilisation – ↑ glucagon, ↓ insulin • 3 locations for oxidation in the liver – peroxysomal β-oxidation – mitochondrial β-oxidation – ER Ω-oxidation (CYP4a catalysed)
Mitochondrial β oxidation
• Primarily involved in oxidation of FAs of various chain length
• Multistep process
• Progressive shortening into acetyl-CoA subunits
– Condensed into ketone bodies providing oxidisable energy to cells
– Enter tricarboxyl acid cycle – resulting in H2O and CO2
• Regulated by CPT (carnitine palmitosyl transferase), carnitine concentration and malonyl-CoA (which inhibits CPT)
• Genetic disorders inhibiting mitochondrial oxidation, certain drug (incl. Alcohol) and toxins lead to hepatic steatosis
Peroxisomal β oxidation
• Main role is detoxification of
– very long chain fatty acids (>C 20)
– 2-methyl-branched FAs
– Dicarbolic acids – very toxic – inhibiting mitochondrial fatty acid oxidation
– Prostanoids
– C-27 bile acid intermediaries
• 4 step process is repeatedly performed to shorten chain length. Each step can be carried out by at least 2 enzymes
• Several enzyme are induced by PPARά
• Disruption leads to micro-vesicular steatosis
Microsomal Ω -oxidation
- Normally a minor metabolic pathway but in fat overload increases
- CYP4A enzymes oxidise saturated and unsaturated fatty acids
- Ω-hydroxylation in the ER, followed by decarboxylation of the Ω-hydroxy fatty acid in the cytosol – in turn enter the β-oxidation pathway
- Dicarboxyl FA act as ligands to PPARά – induction of the oxidation systems
Regulation at molecular level
• FAs regulate gene expression by controlling activity of key transcription factors (TF)
• Several TFs have been identified
– Peroxisome proliferator-activated receptors
(PPAR ά, β and γ)
– Retinoid X receptor (RXR)
– Sterol regulator element binding protein (SREBP)
• TFs have various functions:
– Integration of signals from diverse pathways
– Co-ordination of the metabolic machinery for FA metabolism
Peroxisome proliferator activated receptor (PPAR)
• All PPARs (ά, γ,β/ δ) are involved in lipid homeostasis
• PPAR ά and β/ δ facilitate energy combustion
• PPAR γ facilitates energy storage
• PPAR ά is a lipid sensor – gene transcription
• Reduced PPAR ά sensing/activity leads to steatosis, possible by induction of CYP2E1, proinflammatory cytokines and TFN ά
Balance
• Health / short-term excess
– Equilibrium
– Energy combustion > energy storage
• Disease (e.g. diabetes) / persistent or gross overload
– Balance disrupted
– Increased Energy storage -> adiposities
– Lipotoxicity
Developing fatty liver
• Increase plasma in fatty acids (mainly in TG)
– Excess dietary fat intake
– Excess dietary caloric intake overall
• But also increased flux of FAs
– Increased release of FAs from adipocytes
– Increased FA uptake in hepatocytes
• Decreased FA oxidation
• Decreased demand for lipids for fuel leading to
increased storage
• Resulting in bland steatosis
• Insulin resistance augments the process
Incidence of NAFL
• Overstorage of unmetabolised energy exceeding the energy combustion capability of the PPAR a mediated system
• Hepatic steatosis – fat content exceeding 5-10 % the weight of the liver
• Incidence:
– 50 % diabetic patients
– 75 % of obese patients
– 98 % of morbidly obese patients
Steatohepatitis
- Increased steatosis (bland)
- Apoptosis of fat-laden hepatocyte releases TG and toxic FAs
- FAs induce CYP2E1 & FA oxidation systems →generation of reactive oxygen species (ROS) resulting in oxidative stress
- Oxidative stress induces release of proinflammatory cytokines from Kupffer cells (hepatitis) and ROS (and ethanol) activates stellate cells (fibrogenesis)
- Lipidperoxidation products develop immunogenic properties causing inflammation
- Gut derived products (e.g. endotoxins) also activate Kupffer cells
Management of fatty liver disease
• Diet and exercise – ↓ Supply - Reduced intake of calories – ↑ Demand – increased consumption – The body will get energy from the “compartment” least in demand e.g. • Exercise – fat burning • Illness – muscle protein utilisation
Alcohol and fatty liver
• Alcohol beverages are high in calories but most contain no fat
• However alcohol is the classic cause of fatty liver
Alcohol and liver fat
• High caloric load – energy load
• Metabolised in the liver – increased load leads to:
• Impairment and inhibition of PPARά and SREBP
– PPARά ↓ - ↓ fat oxidation
– SREBP ↓ - ↑ FAS - lipogenesis
• Damage to cell organelles – mitochondria, ER – reduced fat oxidation
• Apoptotic hepatocytes release TG and very-long chain FA – augment liver injury
• Stellate cell activation –leading to increased fibrogenesis
