Ectopic lipids and non-alcoholic fatty liver disease(NAFLD) Flashcards
What is ectopic fat?
What are the main types of fat storage?
- Fat (lipids) stored in places not designed for mass storage (i.e. not adipose tissue).
- Sites of fat storage:
1. Subcutaneous adipose tissue (ScAT) - located just under the layer of skin, safest/lowest CVD risk
2. Visceral adipose tissue (VAT) - deeper in abdomen, around organs associated with increased CVD risk
3. Intra-organ - stored within organs, associated with higher CVD risk
2&3 are classed as ectopic as it is only over a short time period
How does the body adapt to low PA and increased sedentary behaviour?
- Body buffers excess energy by storing as adipocytes
- When finite capacity is reached, adipose tissue becomes dysfunctional, causes inflammatory reaction
- Insulin is important for metabolic homeostasis, cannot effectively uptake lipids into tissue (adipose tissue lipolysis) - increases breakdown of FFA
- Lipids then delivered to ectopic sites, e.g.: skeletal muscle which is involved in many metabolic diseases
- Hypoxia- when adiposities become starved of o2
Describe how ectopic fat accumulates:
- increase energy intake/decrease energy expenditure
- increased: inflammation, hypoxia, proinflammatory cytokines, insulin resistance
- fat spill over (FFA) into liver, skeletal muscle, pancreas and heart
What percentage of the population are likely to develop:
- Hepatic steatosis
- NASH(Non-alcoholic steatohepetitus)
- Cirrhosis
- 32%
- 10-30%
- 10-15%
- mainly related to obesity
What is de novo lipogenesis?
What activates de novo lipogenesis?
- The formation of lipids in the liver from non-lipid precursors
- increased blood insulin & glucose
- glucose and fructose from the poor diet can both be used in DNL
What are the 3 main supply roots for hepatic steatosis?
Describe the pathogenesis of hepatic steatosis:
- Dysfunctional adipose tissue
- TAG-rich chylomicrons
- insulin resistant skeletal muscle
- High dietary fat = increased lipolysis(in adipose tissue) –> more FFA in blood to be taken up by liver
- High fat could also be transported to liver by TAG chylomicrons for increased TAG synthesis
- High dietary fructose & glucose induce de novo lipogenesis = increased hepatic FFA
- also caused by skeletal muscle insulin resistance = more insulin to combat glucose in blood –> causing DNL
Describe non-alcoholic fatty liver disease:
- Is the excessive storage of ectopic fat in the liver
- referred to as NAFLD when fat accumulation occurs in the absence of high alcohol consumption. - is fully reversible, strongly correlated with hepatic and whole body insulin resistance
- In obese people, the prevalence of NAFLD may be as high as 50–70%
What body changes cause hepatic fat accumulation?
- NEFA plasma concentrations
- Lipid originating from a meal
- De novo lipogenesis (DNL)
- Hepatic export of VLDLs or
- Hepatic fat oxidation
Describe NEFA:
- higher plasma NEFA concentrations (from elevated adipose tissue lipolysis) = higher hepatic NEFA influx = higher hepatic triacylglycerol (TAG) content
- Obese people with high intrahepatic lipid (IHL) content have a twofold higher rate of lipolysis than obese people with normal IHL content
- high fasting NEFA concentrations associated with obesity might contribute to elevated IHL content.
- impaired insulin suppresses lipolysis which may be an underlying factor in NAFLD
How is NAFLD diagnosed?
- through a liver biopsy
- gold standard = visible lipid droplets in >5% of hepatocytes
- but is invasive and needs a specialist
- also through MRI, CT and blood biochemistry as they can detect inflammation
What is the prevalence of NAFLD in the following populations:
- T2DM
- Obesity
- Severe obesity
- Currently affects ~32% of adults. Increased due to:
➢ Type 2 diabetes: ~60%
➢ Obesity (BMI ≥ 30kg/m2): ~70%
➢ Severe obesity (BMI ≥ 40kg/m2): >90% - Individuals with NAFLD are at a two-fold greater risk of developing T2D in the future. Shared mechanisms with insulin resistance
What is the impact of NAFLD? What other metabolic diseases is it closely related to?
- T2DM
- cardiovascular disease
- insulin resistance
- dyslipidaemia - large quantities of lipid in the blood stream
- hypertension
Define hepatic steatosis:
How does it develop?
- accumulation of liver fat
- Hepatic steatosis develops when lipid supply to the liver exceeds the ability to dispose of it.
- when supply(adipose tissue lipolysis, dietary fat & de novo lipogenesis) outweighs disposal(fat oxidation & VLDL-TAG export)
What are the current mechanisms suggested to manage NAFLD?
- Lifestyle modifications, which include diet and physical activity to achieve weight loss, remain the first-line treatment for NAFLD.
What are the 2 lifestyle modification guidelines for people with NAFLD?
- weight loss ≥ 5% total BM can reduce hepatic steatosis by ≥ 7% can lead to NASH resolution and ≥10% can result in fibrosis regression or stability –> more weight loss = greater benefit on physical health
- Regular physical activity for patients with NAFLD, (150-300 minutes of moderate-intensity) or (75-150 minutes of vigorous-intensity aerobic exercise per week).
➢ Resistance training can have independent beneficial effects on NAFLD.
➢ The impact of exercise on NAFLD can enhance the positive effect of a hypocaloric diet.
What is the association between body weight and presence of NAFLD?
How is this related to insulin sensitivity?
- More body weight lost, the more liver fat lost
- each 1% reduction in BM = 0.9% absolute reduction in liver fat
- Reduction in liver fat correlated with increase in peripheral insulin sensitivity
Describe the relationship between exercise and IHL(intra-hepatic lipids):
exercise-related EE induces negative energy balance, resulting in ↑ mobilisation of hepatic lipids to fuel deficit.
* Exercise may have weight-independent effects by influencing the supply / disposal routes of hepatic lipids
- decreased in energy intake throughout the exercise training programme might have been responsible for reduced BMI and fat mass, rather than the exercise training programme itself.
What are the mechanisms in which exercise reduces adipose tissue lipolysis?
- mainly in a fed state exercise improves adipose tissue insulin sensitivity = suppressed lipolysis
- causing less FA to be transported to the liver for NASH
What are the mechanisms in which exercise reduces NASH through skeletal muscle actions?
- increase uptake & oxidation of FFA
- increase lipid uptake directly from diet via increased LPL activity
- increase glucose uptake from blood because of enhanced insulin sensitivity
= lower blood glucose for DNL in liver
Describe how the liver supply of lipids is blunted by exercise:
- ↓ uptake of lipids from the circulation (↓ hepatic lipase activity)
➢ Difficult to measure directly in humans, most in rodent, animal experiments - ↓ DNL
➢ No evidence in humans; reduced enzyme activity in rodents (SREBP-1c, FAS, ACC)
➢ Reduced circulating glucose & insulin
Describe how liver disposal is effected by exercise:
- ↑ lipid oxidation
➢ No evidence in humans; ↑ markers of β-oxidation and mitochondrial biogenesis in rodents, suggests increase rate and increased mitochondrial function - VLDL-TAG export - may be decreased as a consequence of low lipid availability in the liver, so less VLDL to export
➢ Limited evidence potentially showing decrease rather than increase
What are the mechanisms that resistance & aerobic exercise can regulate liver fat:
- Hypertrophy of type II muscle fibres
➢ Type II fibres characterised by anaerobic glycolytic metabolism.
➢ Hypertrophy = greater glycolytic demand from muscle.
➢ ↓ circulating glucose meaning less substrate for DNL in liver - Activation of GLUT4 and AMPK
➢ GLUT4 = insulin-regulated transporter protein responsible for glucose uptake into muscle.
➢ AMPK = energy-sensing kinase which promotes insulin sensitivity. Activated in periods of energy deficit
➢ Enhanced insulin sensitivity ↑GLUT4-mediated glucose uptake into muscle which ↓ circulating glucose and insulin (activators of DNL). - Alteration in myokines
➢ Myokine = cytokine which is produced and secreted by skeletal muscle.
➢ Irisin is a myokine which is increased by resistance exercise.
➢ Suggested to modulate fat metabolism in liver by inhibiting key regulators and enzymes involved in DNL (SREBP-1c, FAS) - reduces newly produced lipids in the liver
Is ectopic fat bad?
Why is its health risk different in non-athletic populations?
- Skeletal muscle lipids are elevated (myosteatosis) in endurance athletes & T2DM individuals compared to sedentary counterparts.
- athletes remain highly insulin sensitive (cardio metabolically healthy) whilst individuals with T2DM exhibit insulin resistance.
- This may be beneficial in athletes where the fuel demand is large.
- The form of lipids stored in the muscle dictates metabolic outcomes (e.g. PUFA(athletes) vs. Saturated FA (sedentary).
