Week 8 ectopic lipid and NAFLD

Question 1

What is ectopic fat?

Answer 1

Fat stored where it is not supposed to be (i.e. outside adipose tissue)

*one issue with the definition is many people would consider visceral adipose tissue to be ectopic

Question 2

What is intra-organ ectopic fat?

Answer 2

Fat stored within the organs

Question 3

What are some of the sites of ectopic storage?

Answer 3

Hepatic lipid accumulation in the liver (insulin resistance)

Muscle

Pancreatic beta cell (hyperglycaemia)

Perivascular fat in veins/arteries(altered blood flow)

Heart

Kidneys

Question 4

What is hepatic steatosis?

Answer 4

Accumulation of fat (intrahepatic, triglycerides and IHTG) in the liver

Question 5

Non alcoholic fatty liver disease (NAFLD) is a spectrum of conditions, what is the order of this spectrum?

Answer 5

Healthy liver –> Hepatic steatosis –> Non alcoholic steaso hepatitis (inflammation) –> Cirrhosis –> Hepato-cellular carcinoma (liver transplant/death)

Question 6

When is hepatic steatosis diagnosed?

Answer 6

When IHTG percentage is >5% (approx. 1% in normal healthy people)

Presence of TG in >5% of hepatocytes (liver biopsy)

IHTG content >5.56% (MRI or 1H-MRS)

Question 7

Why did NASH go unrecognised for many decades and what happened in 1980 to change that?

Answer 7

Doctors confused it with alcoholic steatohepatitis

The large number of children found to have NASH helped dispel any lingering doubts

Question 8

What is the prevalence of NAFLD?

Answer 8

Most common form of liver disease worldwide

Affects 25% of adults
7-16% in normal weight adults with no risk factors
70% in obese adults (BMI > 30kg/m2)
>90% in obese adults with T11D

Increasingly common in children (17% of 15-19yr olds)

Question 9

Advanced NAFLD is the second most common cause of what?

Answer 9

Liver transplant (increasingly likely to become the most common)

Question 10

What are some risk factors for NAFLD?

Answer 10

High BMI
Increased central/abdominal fat
Age
Physical inactivity 
Ethnicity (Hispanic > South Asian > White European > Afro-Caribbean)
Certain genetic risk variants

Question 11

NAFLD is linked with other health complications, what are some of these?

Answer 11

T11D
CVD
Hypertension
Dyslipidaemia
Chronic kidney disease

Question 12

What is pathogenesis?

Answer 12

Liver fat percentage (IHTG) is regulated by the amount of lipid supplied to the liver and its ability to utilise it appropriately.

If lipid supply is higher than lipid utilisation it will be stored in the liver as IHTG.

Question 13

What are some sources of hepatic lipid supply?

Answer 13

Circulating dietary lipids (TAG-rich chlyomicrons)

Circulating NEFA from lipolysis of adipose tissue

De novo synthesis (de novo lipogenesis DNL) from dietary glucose

Question 14

What are some sources of hepatic lipid utilisation?

Answer 14

Oxidation

Export (as L-TAG)

Question 15

What is meant by the athlete paradox?

Answer 15

Athletes have a high intra-muscular triglyceride content (suggests not all ectopic fat is bad)

Goodpaster et al (2001) found that highly trained athletes had a higher IMCL than the obese group.

Question 16

What is the association between NAFLD and T11D?

Answer 16

NAFLD is an independent predictor of T11D

People with NAFLD 2-5x more likely to get T11D than those without.

Over 14 years, 50% of people with steatosis developed T11D (>70% in those who had NASH)

But 1 in 4 people with NAFLD have T11D (its not an instant inevitability)

Question 17

Summarise TAG synthesis and lipotoxicity

Answer 17

When we have an obese group we get an increase in free fatty acids

There is an increase in DAG because conversion to TAG cant fully account for it

This leads to an increase in protein kinase C isoforms (PKCO) which contributes to insulin resistance and less efficient insulin signalling (decreased P-Akt / IRS-2-P)

Question 18

Metabolic roles of insulin - when does glycaemic control occur?

Answer 18

When there is increased circulating glucose

Question 19

Metabolic roles of insulin - what is glycaemic control?

Answer 19

Suppresses endogenous glucose production (liver) (after a meal we don’t need to rely on stored glucose in the liver as we can use dietary glucose)

Stimulates glucose uptake (muscle, adipose tissue)

Question 20

Metabolic roles of insulin - when does lipid metabolism occur?

Answer 20

When there is increased circulating lipids

Question 21

Metabolic roles of insulin - what is lipid metabolism?

Answer 21

Suppresses lipolysis / fatty acid release into the circulation (adipose tissue)

Stimulates lipoprotein lipase (LPL) to enhance lipid storage (adipose tissue)

Suppresses hepatic apolipoprotein B-11 and VLDL-TAG secretion (liver)

Question 22

Metabolic roles of insulin - when does protein metabolism occur?

Answer 22

When there is reduced skeletal muscle mass / function (sarcopenia)

Question 23

Metabolic roles of insulin - what is protein metabolism?

Answer 23

Inhibits protein breakdown (muscle)

Stimulates protein synthesis (muscle)

Question 24

How does insulin stimulate skeletal muscle glucose uptake in a healthy body?

Answer 24

Insulin binds to insulin receptor –> phosphorylates IRS1 (insulin receptor substrate 1) –> activates P13Kinase –> stimulates translocation of GLUT4 vesicles to the cell membrane –> these vesicles allow glucose into the cell to be stored

Question 25

What happens when we have an accumulation of DAG in the muscle?

Answer 25

It activates PKC0 which disrupts phosphorylation of IRS1 so GLUT4 vesicle stay within the cell which essentially means glucose cant enter the cell which leads to insulin resistance

Question 26

How does an accumulation of DAG affect the liver?

Answer 26

When we're fasted we break down stored glycogen into glucose to be used for metabolism When we have meal we want to switch this process off (insulin binds to IRS2 which stimulates P13K which activates Akt2 which stops the process) This is disrupted when we have an accumulation of DAG and the liver continues to release glucose even though we've just had a dietary supply.

Question 27

What are some impacts of accumulated DAG (aside those to the muscle and liver)?

Answer 27

Increases inflammation (which can further promote insulin resistance) Activates the unfolded protein response which causes endoplasmic reticulum stress (again promotes insulin resistance).

Question 28

What are the characteristics of endurance trained skeletal muscle?

Answer 28

Lots of lipid droplets but they're not full Big / more mitochondria (ready to utilise fat) Lots of proteins / enzymes so lipids can work way into mitochondria efficiently to produce energy.

Question 29

What are the characteristics of skeletal muscle in a person with T11D?

Answer 29

Bigger, fuller lipid droplets Smaller / fewer mitochondria Lipid droplets sit on their own, not near the mitochondria Don't have an up-regulation of required proteins / enzymes

Question 30

What is the relationship between insulin action and intrahepatic triglyceride content?

Answer 30

As liver fat goes up, insulin sensitivity goes down

Question 31

What is the relationship between weight loss and NAFLD?

Answer 31

A study by the EASL found that weight loss (average 5-6Kg in this study) was associated with a remission of NAFLD As people lost more weight the chances of resolving NAFLD increased Out of the people who lot more than 10% of their body weight, 97% had a resolution in NAFLD. People who lose more eight also likely to reverse T11D

Question 32

What are some of the mechanisms by which exercise may reduce IHTG in NAFLD? * possibly but evidence inconclusive ** positive evidence but in rodents

Answer 32

Increased energy expenditure (but comparatively small vs diet) Modulate supply / utilisation of lipids in the liver * Reduce basal rates of adipose tissue lipolysis * Improved post-prandial lipid metabolism (but only if exercise is regular) Improved hepatic lipid oxidisation ** Reduced de novo lipogenesis ** Improvements in peripheral insulin sensitivity