NAFLD

Question 1

Describe the disease progression of NAFLD

Answer 1

Healthy liver –> Fatty liver (steatosis, NAFL) –> Hepatic inflammation and necrosis (nonalcoholic steatohepatitis, NASH) –> Progressive fibrosis (nonalcoholic cirrhosis; irreversible)

Question 2

Describe the “Two-Hit” hypothesis of NAFLD pathogenesis

Answer 2

Fat accumulation (steatosis) is the first hit, which makes the liver vulnerable to the second hit, including oxidative stress and proinflammatory cytokines (like TNF)

Question 3

How does fatty liver (“first hit”) develop?

Answer 3

Obesity and insulin resistance - Liver gets fat from CHO (de novo lipogenesis), chylomicrons, FFAs from lipolysis); liver disposes of them via VLDL and b-oxidation; if have imbalance between these tow functions you have fat accumulation in the liver

Question 4

What are the two types of insulin resistance that contribute to development of fatty liver?

Answer 4

• Peripheral IR

* Hepatic IR

Question 5

Give a general outline of how peripheral insulin resistance contribute to steatosis?

Answer 5

Specifically adipose tissue IR promotes fatty liver development.
• Insulin inhibits lipolysis, IR compromises this and puts a lot of fatty acids into circulation (hyperglycemia)

Question 6

Describe the mechanisms underlying adipose tissue IR

Answer 6

• Obesity, featured by adipose tissue enlargement, is assoc with adipose tissue dysfunction
• Adipose tissue dysfunction, mainly manifested by IR, results from chronic low-grade inflammation and/or oxidative stress in adipose tissue

Question 7

What can happen when adipose tissue has IR?

Answer 7

• Insulin exerts suppressive effect on lipolysis, so one consequence of adipose tissue IR is UNCONTROLLED LIPOLYSIS
• Increased plasma FFAs lead to increased hepatocyte uptake –> increased TG synthesis and secretion –> fatty liver and hypertriglyceridemia (cause for CVD)

Question 8

Name two hepatic factors contributing to NAFLD

Answer 8

• Up-regulation of de novo lipogenesis pathway (due to hyperinsulinemia)
• Inhibition of fatty acid b-oxidation (due to mitochondrial dysfunction)

Question 9

Describe what hepatic insulin resistance does to the body/liver

Answer 9

• IR is assoc with hyperglycemia and hyperinsulinemia
• Insulin SUPPRESSES GLUCONEOGENESIS, so hepatic insulin resistance is assoc with uncontrolled glucose release by hepatocytes, a main cause for fasting hyperglycemia in diabetes
• Insulin ACTIVATES DE NOVO LIPOGENESIS by activating SREBP-1c, so IR in liver can alleviate de novo lipogenesis, leading to ameliorated fat accumulation in the liver

Question 10

Describe selective insulin resistance

Answer 10

(aka pathway specific insulin resistance)

• In IR mouse models, insulin fails to suppress gluconeogenesis but continues to promote lipid synthesis.
• This selective hepatic IR contributes to hyperglycemia and hyperlipidemia