Module 7: Liver Role in Metabolic Disease

Question 1

Dominant fat in the diet

Answer 1

Triacylglycerols (TAG)

Question 2

TAG digestion

Answer 2

Tag –> 1FA+1DAG –> 2FA+1MAG

Question 3

2 primary bile acids

Answer 3

-cholic acid (CA)
-chenodeoxycholic acid (CDCA)

Question 4

Where are primary acids made and stored

Answer 4

made in liver stored in gallbladder

Question 5

2 bile salts and how are they formed

Answer 5

-Taurochenodeoxycholic (TCA)
-Glycochenodeoxycholic (GCDCA)
conjugated w taurine or glycine in LIVER

Question 6

What happens to bile salts in the small intestine

Answer 6

-deconjugated by gut bacteria
-break conjugate bonds
(necessary for recycling bile acids)

Question 7

What happens to bile salts in the large intestine

Answer 7

Further metabolized to form secondary bile acids
-more hydrophobic

Question 8

2 secondary bile acids

Answer 8

-deoxycholic acid (DCA)
-lithocholic acid (LCA)

Question 9

Why do bacteria deconjugate bile acids

Answer 9

1. detoxify bile acids
2. release atoms (carbon,nitrogen,sulfur) used by microbiota directly

Question 10

What do bile acid resins do

Answer 10

-bind bile acid in digestive tract to prevent enterohepatic circulation
–> causes activation of CYP7A1 neural path

Question 11

what does neural pathway CYP7A1 do

Answer 11

-Increased conversion of hepatic cholesterol into bile acids.
– Depletion of hepatic cholesterol levels –> increased uptake of bl cholesterol into
the liver.
– Lowering total cholesterol and LDL-cholesterol in blood

Question 12

what does FXRα do

Answer 12

regulates gluconeogenic genes and hepatic glucose production (HGP)

Question 13

Orlistat

Answer 13

inhibitor that alters fat absorption -inhibits both pancreatic and gastric lipases in digestive tract

Question 14

Outcomes of taking orlistat(2)

Answer 14

-reduced triglyceride uptake
-increased fat excretion

Question 15

Different stages of T2D

Answer 15

Healthy
-normal glu and ins
IR
-normal glu, high ins
Type 2(early)
-high glu and ins
Type 2(late)
-high glu, low ins

Question 16

How to assess insulin sensitivity

Answer 16

1.Mathematically (homeostatic model
assessment)
2.Glucose/insulin clamp
3.OGTT

Question 17

1.Mathematically (homeostatic model
assessment)

Answer 17

Uses fasting glucose and fasting insulin values
* Estimates
1. HOMA-IR (estimates a person’s insulin resistance)
2. HOMA-β (estimates a person’s insulin secretion)

Question 18

2.Glucose/insulin clamp

Answer 18

Glucose:
-assess insulin secretion by beta cells
-more glucose infused, better insulin secretion
Insulin:
-assess peripheral insulin sensitivity
-more glucose infused, more insulin sensitive

Question 19

OGTT

Answer 19

determines how quick glucose is cleared from blood

Question 20

rank assessment methods based on most reliable

Answer 20

1.Clamp
2.OGTT
3.Math (HOMA)

Question 21

Blood glucose levels maintained through balance of: (3)

Answer 21

– Intestinal absorption (from dietary carbohydrates)
– Uptake by peripheral tissues (adipose, skeletal muscle, etc)
– Clearance / production by liver

Question 22

How does liver plays a major role in blood glucose homeostasis (3)

Answer 22

– Uptake and storage of glucose (glycogenesis)
– Release of glucose (glycogenolysis; gluconeogenesis)
– Hepatic glucose production and glucose release are sensitive to
hormones (e.g., insulin, glucagon, etc.)
– Responsible for 90% of blood glucose in the fasting state

Question 23

Hormonal Regulation of HGP

Answer 23

Insulin release will suppress HGP and inhibit release of glucagon from pancreatic α-cells.Glucagon stimulates HGP.

Question 24

Insulin release from beta cells

Answer 24

1. Glucose enters β-cell via
   GLUT2.
2. Glucose undergoes
   glycolysis (glucose is
   stored), increasing cellular
   ATP levels.
3. High ATP levels shut down
   ATP-sensitive channels,
   causing a depolarization.
4. Depolarization results in
   calcium flooding inside the
   β-cell.
5. Insulin released from
   granules into blood.

Question 25

Phase 1 of insulin release (RRR)

Answer 25

-rapid release of insulin from granules

Question 26

Phase 2 of insulin release (RP)

Answer 26

-production of a new insulin-containing granules

Question 27

Phases of insulin release: obese,insulin sensitive

Answer 27

RRP & RP normal
-obese have higher beta cell mass

Question 28

Phases of insulin release(beta cells): impaired glucose tolerance

Answer 28

RRR depleted, RP normal

Question 29

Phases of insulin release(beta cells): T2D

Answer 29

RRP lost or problem w insulin exocytosis, RP depleted
-pancreatic fatigue

Question 30

insulin/glucose/glucagon after CHO meal: T2D

Answer 30

-high bl glu, low ins, high glucagon

Question 31

insulin/glucose/glucagon after insulin injectionl: T2D

Answer 31

-glucose reduced, glucagon high

Question 32

insulin/glucose/glucagon fed state T2D vs normal

Answer 32

Normal:
-high ins,low glucagon,bl.glu levels maintained thru dietary glu
T2D:
-insulin injected, high glucagon, diet. glu and HGP cause high bl.glu

Question 33

insulin/glucose/glucagon fasting state T2D vs normal

Answer 33

Normal:low ins,high glucagon,HGP maintain bl. glu
T2D:
-low ins,high glucagon, HGP responsible for bl.glu

Question 34

Insulin injection ability to clear bl. glu fed vs fasted

Answer 34

Fasting: injection sufficient to clear bl. glucose
Fed: injection insufficient

Question 35

Insulin: direct regulation of HGP

Answer 35

Insulin released by the pancreas is secreted into the
portal vein to “directly” regulate HGP.
– insulin promotes hepatic glucose uptake (via GLUT2) and the production of glycogen, while inhibiting gluconeogenic enzymes

Question 36

Insulin: indirect regulation of HGP(3)

Answer 36

-Inhibiting glucagon secretion from α-cells in pancreas
– Inhibiting free fatty acid release from adipose tissue
– Altering adipokine secretion (adiponectin inhibits HGP)
– Regulating the hypothalamus-liver axis (communication
between the brain and the liver regulate HGP)

Question 37

Monogenic diabetes -inheritance and what genetic mutation

Answer 37

-autosominal dominant interitance
-nonsense mutation in glucokinase (premature stop codon)

Question 38

Liver-specific insulin receptor (IR)-knockout (LIRKO)

Answer 38

-increase in bl glu
-unable to suppress insulin
*livers think they are in a fasted state

Question 39

How to increase hepatic glucose metabolism in the liver

Answer 39

over-express hepatic glucokinase