Module 7: Liver Role in Metabolic Disease Flashcards
Dominant fat in the diet
Triacylglycerols (TAG)
TAG digestion
Tag –> 1FA+1DAG –> 2FA+1MAG
2 primary bile acids
-cholic acid (CA)
-chenodeoxycholic acid (CDCA)
Where are primary acids made and stored
made in liver stored in gallbladder
2 bile salts and how are they formed
-Taurochenodeoxycholic (TCA)
-Glycochenodeoxycholic (GCDCA)
conjugated w taurine or glycine in LIVER
What happens to bile salts in the small intestine
-deconjugated by gut bacteria
-break conjugate bonds
(necessary for recycling bile acids)
What happens to bile salts in the large intestine
Further metabolized to form secondary bile acids
-more hydrophobic
2 secondary bile acids
-deoxycholic acid (DCA)
-lithocholic acid (LCA)
Why do bacteria deconjugate bile acids
- detoxify bile acids
- release atoms (carbon,nitrogen,sulfur) used by microbiota directly
What do bile acid resins do
-bind bile acid in digestive tract to prevent enterohepatic circulation
–> causes activation of CYP7A1 neural path
what does neural pathway CYP7A1 do
-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
what does FXRα do
regulates gluconeogenic genes and hepatic glucose production (HGP)
Orlistat
inhibitor that alters fat absorption -inhibits both pancreatic and gastric lipases in digestive tract
Outcomes of taking orlistat(2)
-reduced triglyceride uptake
-increased fat excretion
Different stages of T2D
Healthy
-normal glu and ins
IR
-normal glu, high ins
Type 2(early)
-high glu and ins
Type 2(late)
-high glu, low ins
How to assess insulin sensitivity
1.Mathematically (homeostatic model
assessment)
2.Glucose/insulin clamp
3.OGTT
1.Mathematically (homeostatic model
assessment)
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)
2.Glucose/insulin clamp
Glucose:
-assess insulin secretion by beta cells
-more glucose infused, better insulin secretion
Insulin:
-assess peripheral insulin sensitivity
-more glucose infused, more insulin sensitive
OGTT
determines how quick glucose is cleared from blood
rank assessment methods based on most reliable
1.Clamp
2.OGTT
3.Math (HOMA)
Blood glucose levels maintained through balance of: (3)
– Intestinal absorption (from dietary carbohydrates)
– Uptake by peripheral tissues (adipose, skeletal muscle, etc)
– Clearance / production by liver
How does liver plays a major role in blood glucose homeostasis (3)
– 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
Hormonal Regulation of HGP
Insulin release will suppress HGP and inhibit release of glucagon from pancreatic α-cells.Glucagon stimulates HGP.
Insulin release from beta cells
- Glucose enters β-cell via
GLUT2. - Glucose undergoes
glycolysis (glucose is
stored), increasing cellular
ATP levels. - High ATP levels shut down
ATP-sensitive channels,
causing a depolarization. - Depolarization results in
calcium flooding inside the
β-cell. - Insulin released from
granules into blood.
Phase 1 of insulin release (RRR)
-rapid release of insulin from granules
Phase 2 of insulin release (RP)
-production of a new insulin-containing granules
Phases of insulin release: obese,insulin sensitive
RRP & RP normal
-obese have higher beta cell mass
Phases of insulin release(beta cells): impaired glucose tolerance
RRR depleted, RP normal
Phases of insulin release(beta cells): T2D
RRP lost or problem w insulin exocytosis, RP depleted
-pancreatic fatigue
insulin/glucose/glucagon after CHO meal: T2D
-high bl glu, low ins, high glucagon
insulin/glucose/glucagon after insulin injectionl: T2D
-glucose reduced, glucagon high
insulin/glucose/glucagon fed state T2D vs normal
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
insulin/glucose/glucagon fasting state T2D vs normal
Normal:low ins,high glucagon,HGP maintain bl. glu
T2D:
-low ins,high glucagon, HGP responsible for bl.glu
Insulin injection ability to clear bl. glu fed vs fasted
Fasting: injection sufficient to clear bl. glucose
Fed: injection insufficient
Insulin: direct regulation of HGP
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
Insulin: indirect regulation of HGP(3)
-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)
Monogenic diabetes -inheritance and what genetic mutation
-autosominal dominant interitance
-nonsense mutation in glucokinase (premature stop codon)
Liver-specific insulin receptor (IR)-knockout (LIRKO)
-increase in bl glu
-unable to suppress insulin
*livers think they are in a fasted state
How to increase hepatic glucose metabolism in the liver
over-express hepatic glucokinase
