Week 7 - Ectopic lipids and liver disease

Question 1

Various factors that may play a role in determining hepatic fat content

Answer 1

Delivery of lipids to the liver
De novo lipogenesis
Hepatic lipid oxidation
Secretion of intrahepatic lipids to the circulation

Question 2

Hepatic lipid accumulation can occur because of changes in the following

Answer 2

1) NEFA plasma concentrations
2) Lipids originating from a meal
3) De novo lipogenesis (DNL)
4) Hepatic export of VLDLs
5) Hepatic fat oxidation

Question 3

Conditions in which IHL accumulates:

Answer 3

• Increased hepatic NEFA uptake due to higher fasting and/ or postprandial plasma NEFA concentrations
• Low partition of fatty acids to skeletal muscle (low chylomicron clearance by muscle and low NEFA uptake)
• Elevated DNL; activated by elevated plasma glucose and insulin concentrations
• Limited capacity to increase hepatic VLDL–TAG secretion and hepatic mitochondrial oxidation

Question 4

IHL content

Answer 4

IHL content can directly originate from dietary TAG, transported in chylomicron particles. Release and uptake of TAG-containing chylomicrons occur via lipoprotein lipase (LPL), an enzyme located in the endothelium of adipose tissue and skeletal muscle.
Alternatively, dietary TAG can reach the liver via chylomicron–TAG ‘spillover’ into the serum NEFA pool after incomplete lipolysis via LPL in the adipose tissue and skeletal muscle

Question 5

Effects of exercise training on IHL content:

Answer 5

• Consistently, in obese, sedentary adults, 16 weeks of aerobic exercise training five times a week decreased IHL content by 10% in the absence of weight loss.
• In addition, resistance exercise training for 8 weeks was found to reduce IHL content by 13% in obese, sedentary adults
  The simplest view is that the increase in energy expenditure due to physical activity simply induces a negative energy balance, which in turn may result in the mobilisation of hepatic lipids as a substrate to fuel the energy deficit.
• Hepatic lipid accumulation originates due to changes in the delivery of lipids to the liver, changes in hepatic lipid oxidation, changes in the secretion of IHLs to the circulation or a combination of these factors.

Question 6

NEFA:

Answer 6

• Endurance trained individuals are characterised by low fasting plasma NEFA concentrations (Phielix et al 2012), suggesting that regular exercise may have an effect on adipose tissue lipid NEFA uptake and lipolysis.
• It is well established that endurance training improves whole-body fat oxidation and that this is accompanied by higher plasma NEFA uptake in skeletal muscle. With exercise training, this increased capacity for plasma NEFA uptake into the myocyte has been associated with an upregulation of membrane-associated plasma NEFA transport proteins.

Question 7

Lipids originating from a meal:

Answer 7

Exercise training lowers the serum TAG response to a fatty meal and the prevalence of postprandial hypertriacylgcerolaemia is significantly higher in sedentary people than in trained people.
* The reduction in postprandial hypertriacylycerolaemia associated with endurance exercise adaptions is due to a decrease in chylomicron-TAG half life.
* The difference in TAG half-life between athletes and sedentary men is most probably due to a direct effect on exercise training on LPL-mediated TAG removal to skeletal muscle

Question 8

Key effects of exercise training on pathways that influence IHL content:

Answer 8

• Plasma NEFA:
• Increase in plasma NEFA uptake by skeletal muscle
• Some evidence for decrease in fasting and/or postprandial plasma NEFA
• Dietary TAG:
• Increase in LPL-mediated TAG uptake by skeletal muscle
• Decrease in HL-mediated TAG uptake by liver
• DNL:
• Decrease in plasma insulin, a key player for the activation of DNL
• In diabetes, exercise can decrease plasma glucose and hence decrease DNL
• Lower ACC and FAS protein content, indicative for decreased de novo lipolysis activity (rodent data)
• VLDL metabolism:
• Decrease in hepatic VLDL–ApoB100 and VLDL–TAG secretion, possibly as a consequence of lower hepatic TAG accumulation
• Mitochondrial oxidation:
• Increase in hepatic CS, β-HAD and Cyt c, indicative for increases in hepatic mitochondrial content and oxidative phosphorylation

Question 9

Effects of acute exercise on IHL content:

Answer 9

In both healthy lean individuals and in overweight untrained men hepatic VLDL–TAG secretion and clearance were reduced during exercise and in the early recovery phase. Furthermore, because VLDL–TAG secretion and clearance were both reduced to a similar extent, plasma VLDL–TAG concentrations were not changed. Therefore, it can be suggested that, in the early recovery phase, changes in VLDL–TAG secretion and/or clearance do not contribute to decreases in plasma TAG levels

Question 10

Conclusions

Answer 10

• NAFL develops due to higher hepatic fat availability and synthesis, which is not fully compensated by increased secretion and oxidation of hepatic TAG.
• Exercise training lowers IHL content most likely via a reduction in hepatic fat availability and synthesis, and an increase in hepatic TAG oxidation.
• A single bout of exercise seems to increase rather than decrease IHL content and elevated plasma NEFA during exercise and in the post-exercise period might be the main determinant.

Question 11

gut barrier dysfunction and a “leaky gut”

Answer 11

• Exercise training also impacts the microbiome and gut-liver-axis dysfunction Patients with NAFLD have significant dysbiosis with an overabundance of Gram negative bacteria, which can lead to gut barrier dysfunction and a “leaky gut”
• After as little as 20 weeks of moderate-intensity aerobic exercise training, many beneficial effects have been observed on the gut liver-axis in patients with NAFLD, including reversal of dysbiosis with the restoration of healthy bacterial balance as well as improvements in alpha (species richness) and beta diversity (species diversity).

Question 12

The ACSM has established guidelines to determine when a medical referral is recommended before starting an exercise training program (Thompson et al 2013). These guidelines rely on the following:

Answer 12

Current exercise participation; history and symptoms of cardiovascular, metabolic, or renal disease; and the desired exercise intensity for the person who wants to initiate a physical activity program.
* Currently, at least 150 min/week of moderate or 75 min/week of vigorous-intensity physical activity are recommended for all patients with NAFLD.
* If a formal exercise program is to be used, the combination of aerobic plus resistance training is preferred, albeit emerging data suggests that HIIT can be considered in select patients instead.