Week 8 ectopic lipid and NAFLD Flashcards
What is ectopic fat?
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
What is intra-organ ectopic fat?
Fat stored within the organs
What are some of the sites of ectopic storage?
Hepatic lipid accumulation in the liver (insulin resistance)
Muscle
Pancreatic beta cell (hyperglycaemia)
Perivascular fat in veins/arteries(altered blood flow)
Heart
Kidneys
What is hepatic steatosis?
Accumulation of fat (intrahepatic, triglycerides and IHTG) in the liver
Non alcoholic fatty liver disease (NAFLD) is a spectrum of conditions, what is the order of this spectrum?
Healthy liver –> Hepatic steatosis –> Non alcoholic steaso hepatitis (inflammation) –> Cirrhosis –> Hepato-cellular carcinoma (liver transplant/death)
When is hepatic steatosis diagnosed?
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)
Why did NASH go unrecognised for many decades and what happened in 1980 to change that?
Doctors confused it with alcoholic steatohepatitis
The large number of children found to have NASH helped dispel any lingering doubts
What is the prevalence of NAFLD?
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)
Advanced NAFLD is the second most common cause of what?
Liver transplant (increasingly likely to become the most common)
What are some risk factors for NAFLD?
High BMI Increased central/abdominal fat Age Physical inactivity Ethnicity (Hispanic > South Asian > White European > Afro-Caribbean) Certain genetic risk variants
NAFLD is linked with other health complications, what are some of these?
T11D CVD Hypertension Dyslipidaemia Chronic kidney disease
What is pathogenesis?
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.
What are some sources of hepatic lipid supply?
Circulating dietary lipids (TAG-rich chlyomicrons)
Circulating NEFA from lipolysis of adipose tissue
De novo synthesis (de novo lipogenesis DNL) from dietary glucose
What are some sources of hepatic lipid utilisation?
Oxidation
Export (as L-TAG)
What is meant by the athlete paradox?
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.
What is the association between NAFLD and T11D?
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)
Summarise TAG synthesis and lipotoxicity
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)
Metabolic roles of insulin - when does glycaemic control occur?
When there is increased circulating glucose
Metabolic roles of insulin - what is glycaemic control?
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)
Metabolic roles of insulin - when does lipid metabolism occur?
When there is increased circulating lipids
Metabolic roles of insulin - what is lipid metabolism?
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)
Metabolic roles of insulin - when does protein metabolism occur?
When there is reduced skeletal muscle mass / function (sarcopenia)
Metabolic roles of insulin - what is protein metabolism?
Inhibits protein breakdown (muscle)
Stimulates protein synthesis (muscle)
How does insulin stimulate skeletal muscle glucose uptake in a healthy body?
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
What happens when we have an accumulation of DAG in the muscle?
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
How does an accumulation of DAG affect the liver?
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.
What are some impacts of accumulated DAG (aside those to the muscle and liver)?
Increases inflammation (which can further promote insulin resistance)
Activates the unfolded protein response which causes endoplasmic reticulum stress (again promotes insulin resistance).
What are the characteristics of endurance trained skeletal muscle?
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.
What are the characteristics of skeletal muscle in a person with T11D?
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
What is the relationship between insulin action and intrahepatic triglyceride content?
As liver fat goes up, insulin sensitivity goes down
What is the relationship between weight loss and NAFLD?
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
What are some of the mechanisms by which exercise may reduce IHTG in NAFLD?
- possibly but evidence inconclusive
** positive evidence but in rodents
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
