Metabolism 3 – Lipid and liver metabolism & pathologies Flashcards
What are the 3 sources of lipids in the body
- Ingested via diet
- Liberated from adipose tissues (via lipolysis)
- Synthsised in the liver (via de novo lipogenesis)
What occurs to glycerol under fasted conditions
Under fasted conditions, glycerol can be metabolised to generate ATP (in fat, liver, muscle)
How are fatty acids metabolised
Fatty acids are metabolised to ketone bodies via beta oxidation (in the liver)
What occurs to glycerol and fatty acids under fed conditions
Under fed conditions, glycerol and fatty acids are converted to triglycerides for storage
How are lipids mobilised and processed
Lipids are mobilised and processed by lipoproteins and pancreatic hormones
What are lipoproteins
Lipoproteins are vehicles for shuttling water-insoluble lipids (fatty acids, monoglycerides, fat-soluble vitamins, and cholesterol) around the body
What are lipoproteins made up of
All made up of the same basic components; cholesterol, triglycerides, (glycero)phospholipids and proteins
Explain the funciton of Apolipoproteins
- Apolipoproteins act to stabilise and solubilise lipoprotein structures and mediate interactions with lipoprotein receptors to support lipoprotein uptake and clearance
- Apolipoproteins bind lipids to
form lipoproteins - Solubilise lipids for transport in
lymph and blood vessels
What are the 5 different Lipoproteins
From Largest to smallest:
1. Chylomicron
2. VLDL
3. IDL
4. LDL
5. HDL
What are Chylomicrons
Chylomicrons: formed in small intestine following digestion, absorbed into lymph vessels, and deliver triglycerides into bloodstream or liver
What are VLDLs
VLDLs: Very low-density lipoproteins, made in the liver from chylomicrons remnants and other liver lipids. Transport triglycerides
What are IDLs
ILDLs: Intermediate-density lipoproteins, byproducts of VLDLs (via lipoprotein lipase).
Precursor for LDLs
What are LDLs
LDLs: Low-density lipoproteins, “bad cholesterol”, byproducts of VLDL/IDL.
Transport cholesterol
What are HDLs
HDLs: High-density lipoproteins, “good cholesterol”, generated in the liver and intestines via catabolism of VLDLs and chylomicrons.
Function to reverse cholesterol transport
Explain Lipoprotine processing
Dietary fat ->
1. Chylomicrons carry triglycerides from the small intestine to the body’s cells
2. Chylomicron remnant travels to the liver for disassembly
3. VLDL produced by the liver brings more triglycerides to the body’s cells
4. VLDL becomes IDL and then cholesterol-rich LDL as triglycerides are removed
5. LDL delivers cholesterol to the body’s cells
6. HDL picks up excess cholesterol and delivers to the liver for use or disposal
Explain the biosynthesis and actions of cholesterol
- Synthesised from Acetyl-CoA (FFAs precursors)
- Major component of plasma cell membranes
- Precursor for steroid hormones including adrenal, sex and placental hormones
- Aids in production of bile
- Precursor for vitamin D
- Facilitates metabolism of fat-soluble vitamins A, D, E and K
- Insulates nerve fibers (via myelin sheath)
What occurs if there is a DYSREGUALTION OF LIPID METABOLISM
- Dyslipidaemias (including hypercholesterolaemia)
- Fatty liver diseases (NAFLD, cirrhosis)
- Metabolic syndrome (detailed in lecture 2)
Left untreated, lipid disorders can progress to severe CVD and other co-morbidities such as diabetes, fatty liver disease, chronic kidney disease and pancreatitis
Explain Dyslipidaemia
- Defined as ↑ plasma total cholesterol, LDL cholesterol or triglycerides, or a ↓ plasma HDL (or any combination)
- Major risk factor for ischemia heart disease
- Most commonly hypercholesterolemia
- Occurs most often secondary to other conditions (obesity, diabetes mellitus, unhealthy lifestyle), but can also be primary disease (genetic or familial)
- Global prevalence of ~40% in adults (>25 years), and 8th leading risk factor for death (in 2019)
- Equally affects both males and females
How is Dyslipidaemia diagnosed
Diagnosed as one or more of the following (limits vary across laboratories):
- Total cholesterol ≥ 5.5 mmol/L (general population), ≥ 4.0 mmol/L (at risk)
- LDL cholesterol ≥ 2.0 mmol/L (general population), ≥ 1.8 mmol/L (at risk)
- HDL cholesterol < 1.0 mmol/L for men, and < 1.3 mmol/L for women
[Total Cholesterol/HDL ratio > 4.6] - Triglycerides ≥ 2.0 mmol/L
explain the Pathogenesis of Dyslipidaemia
Key points:
- Obesity, and associated hyperglycaemia and hyperinsulinemia (insulin desensitivity), triggers triad of
↑ triglycerides
↑ LDL
↓ HDL
- ↑ FFA from insulin-resistant fat cells leads to increased hepatic production of triglycerides, and consequently, ↑ VLDL
- Lipoproteins change not only in abundance but composition:
Triglycerides in VLDL exchanged for cholesterol esters in HDL/LDL
results in ↑ cholesterol rich VLDL, and triglyceride rich cholesterol depleted HDL - Lipolysis is further disrupted in obesity by ↓ expression of lipoprotein lipase (LPL) in fat and ↓ LPL activity in muscle
[LPL enzyme that breaks down triglycerides to FFA and glycerol] - ↑ FFA also impairs glucose uptake and promote insulin resistance in muscle
What is a major complication of Dyslipidaemia
atherosclerosis
how can Hypertriglyceridemia cause pancreatitis
Hypertriglyceridemia can promote pancreatitis via several pathways:
- Pancreatic lipase overload: Pancreatic lipase helps convert triglycerides into FFAs for absorption. Excessively ↑ triglyceride levels can overwhelm the pancreas with ↑ demands to produce more pancreatic lipase to process the excess fat
- Pancreatic lipotoxicity and inflammation: Excessively ↑ triglycerides leads to fat accumulation in the pancreas known as pancreatic lipotoxicity – leads to inflammation and cellular injury
- Pancreatic duct obstruction: Excessively ↑ triglycerides can lead to the formation of crystals in the pancreatic ducts which physically obstruct pancreatic flux
Patients typically present with severe upper abdominal pain, nausea, fever, elevated heart rate
What are the treatments for Dyslipidaemia
Similarly to T2D, first line therapy is diet and lifestyle interventions
Pharmaceutical interventions include:
- Statins (daily), reduces LDL levels by 25-55% and triglyceride levels 10-20%
- Colestyramine (bile acid binding resin, 1-4x/day), reduces LDL 15-25%, can increase triglyceride levels
- Ezetimibe (daily), reduces LDL 15-25%, option when statins are contraindicated/not tolerated
- Fibrates (1-2x/day), reduces LDL 5-15%, increases HDL 10-30%, decreases triglycerides 40-80% (used in severe hypertriglyceridemia to prevent pancreatitis)
- PCSK9 inhibitors (injectable, once every 2-4 weeks), reduces LDL 20-30% in familial cases, increases HDL
What is NAFLD
- Closely associated with insulin resistance; obesity and metabolic syndrome
- Affects 10-40% adults globally
- Characterised by accumulation of fat in hepatocytes (NAFL: non-alcoholic fatty liver)
- In up to 40% of patients there is also evidence of portal or lobular inflammation and hepatocyte injury (NASH: non-alcoholic steatohepatitis)
- Subset of patients will develop progressive fibrosis → can progress to cirrhosis
- Unmanaged can lead to the development of hepatocellular carcinoma and CV complications
Explain the pathogenesis of NAFLD
- Liver FFA come from 3 sources; diet, de novo lipogenesis, and adipose tissue lipolysis
- In people with fatty livers, ↑ FFA mostly from de novo lipogenesis
- Long chain FFA, products of de novo lipogenesis, are cytotoxic (conversion to triglycerides limits toxicity)
- ↑ FFAs promote cell death via upregulation of death receptors and their ligands → activates extrinsic cell death
- ↑ FFAs can also promote cell death via ER stress/mitochondrial dysfunction → activates intrinsic
cell death - FFA-induced cell death leads to the release of damage-associated
molecular patterns (DAMPs) - Liver fibrosis involves resident and recruited macrophages which respond to DAMPs and release
pro-inflammatory cytokines
What is the progression from NAFLD to cirrhosis
- Healthy liver
- NAFL
- NASH
- Cirrhosis
- Hepatocellular carcinoma
How is NAFLD diagnosed
- No specific biomarker for NAFLD currently available
- Diagnosis therefore based on elimination of all other causes of chronic disease (haemochromatosis, autoimmune hepatitis, alcohol consumption*, medications) * < 30g alcohol/day
- Given comorbidities of NAFLD with insulin resistance and metabolic syndrome, NAFLD should be suspected in all individuals with >1 components of metabolic syndrome
- Most common presentation of NAFLD is detection of unexplained abnormal liver enzymes and/or of bright liver at ultrasonography
- Ultrasound used to diagnose fatty acid infiltration
- Inflammation and fibrosis detected by liver biopsy/histology
What are the treatments for NAFLD
- Like dyslipidaemia, first line intervention for liver steatosis is diet and lifestyle interventions
- Pharmaceutical approaches focus on correcting the underlying cause (insulin resistance, dyslipidemia)
- In severe cases, liver transplantation may be considered
What are Triglycerides?
Triglycerides are fat storage components that can be broken down to fatty acids and glycerol and
metabolised to meet energy demands
What are Lipoproteins made of and what is their primary function
- Lipoproteins are made up of cholesterol, triglycerides, phospholipids and proteins,
It’s primary function to shuttle triglycerides and cholesterol to/from the liver
What is Dyslipidaemia defined as
Dyslipidaemia defined as ↑ plasma total cholesterol, ↑ LDL cholesterol or ↑ triglycerides, or ↓ plasma HDL
(or any combination)
What can chronic dyslipidemia trigger
Chronic dyslipidaemia can trigger the formation of atherosclerotic plaques and CVD, pancreatitis, chronic kidney disease and NAFLD
What is NAFLD associated wtih
NAFLD is associated with fat accumulation in the liver, and can lead to inflammation and fibrosis
NAFLD is strongly associated with dyslipidemia and insulin resistance (that accompany obesity), and
treatments are targeted accordingly
What is NAFLD predominantly driven by
NAFLD is predominantly driven by de novo lipogenesis which can trigger lipotoxicity
