Midterm 3 Flashcards
Risk factors for NAFLD
Non alcoholic fatty liver disease - risk factors include: age, obesity, female gender, hispanic ethnicity, viral hepatitis, iron overload
NASH
Non alcoholic steato hepatitis: inflammation leads to scarring/hardening of liver (fibrosis) which kills liver cells (cirrhosis)
Mechanism by which obesity causes de novo lipogenesis and can lead to fatty liver
Obesity leads to insulin resistance which causes hyperinsulinemia which –> p-ACC –> malonyl CoA increase (which is the basis for fatty acid synthesis)
Mechanism by which obesity causes TG synthesis (and leads to fatty liver)
Obesity leads to insulin resistance which causes hyperglycemia –> chREBP –> TG synthesis (de novo lipogenesis promotes TG synthesis and FA oxidation downregulates it)
Management of NAFLD
- Lifestyle modification (diet & exercise) 2. Weight loss medications 3. bariatric surgery 4. specific NASH drug therapy
ALT
enzyme used to detect liver injury
Perilipin
regulates lipid droplet accumulation and lipolysis
Process that leads to NASH
Lipid droplet gets too big and warps liver cell, warping affects blood flow and reduces oxygen supply, macrophages (kupffer) recruit more immune cells and inflammation –> collagen build up and fibrosis
Characteristics of fatty liver disease
increase in dietary fat, increase in de novo lipogenesis –> increase TG synthesis, also decreased VLDL formation, decreased beta oxidation and decreased lipolysis
Factors that cause NAFLD and NASH respectively
- obesity, overnutrition, inactivity, genetic factors 2. inflammation (metabolites from microbiota and adipokines from adipocytes) ER stress and oxidative stress
Sarcopenia
progressive loss of skeletal muscle mass and strength with risk of adverse outcomes (disability, etc.) especially due to age
How do muscle fibers change in sarcopenia
1) Decreased muscle fiber size- atrophy, 2) decreased number of muscle fibers and 3) selective loss of type 2 fibers
Causes of sarcopenia
Age, disuse, cachexia, neurodegenerative disease, endocrine, nutrition malabsorption
what happens to muscle weight, muscle fiber size and number of muscle cells in sarcopenia?
All decrease
What decreases in sarcopenia?
Muscle weight, type 1 fibers, ESP type 2 fibers, muscle fiber size, muscle cell numbers, muscle stem cells, power produced, anaerobic activity, mitochondrial function and contraction time
What increases in sarcopenia?
Myostatin (which decreases muscle growth and differentiation) and lactic acid consumption
Prevention of sarcopenia
Exercise, increase dietary protein intake, supplement protein after exercise
Sources of arachidonic acid
- membrane phospholipids and 2. dietary intake of omega-6s
Differences between type 1 and type 2 muscle fibers in fuel burned, contraction time
TG vs. ATP and creatine, slow vs. fast
Proinflammatory products coming from omega-6s/arachidonic acid
eicosanoids, prostaglandins, leukotrienes, thromboxanes
Anti-inflammatory products coming from omega-3s
resolvins, protectins and eicosanoids (minimally inflammatory, degrade more rapidly than omega 6 eicosanoids)
4 pathways metabolize arachidonic acid
cyclic pathway, linear pathway and cytochrome p450 pathways (hydroxylase and epoxygenase)
Products of cyclic pathway
synthesis of prostaglandins, prostacyclins and thromboxanes: many of them are pro-inflammatory mediators or play a role in metabolic disorders
Important enzymes of cyclic pathway
Thromboxane synthase, COX1 and COX2
PLA2
enzyme that releases HUFAs (arachidonic acid) from membrane
KO of PLA2
KO decreases adiposity
COX1
necessary for homeostatic functions like GI tract, or kidney function (inhibition undesirable)
COX2
inflammation (inhibition desirable) also sensitizes pain receptors and cancer risk - transcription of COX2 is stimulated by cytokines and growth factors
Corticosteroids
inhibit PLA2
NSAIDS
inhibit COX, divert substrates to LOX and Cyp
Products of linear pathway
Leukotrienes - many are involved in inflammatory and metabolic disorders
Important enzymes of linear pathway
LOX (lipooxygenase)
Products of cytochrome P450 pathway (hydroxylase)
20-HETE - involved in inflammation and hypertension
Products of cytochrome P450 pathway (epoxygenase)
EETs - good metabolite, improve wound healing and reduce inflammation, decrease pain, increase organ regeneration
Hydroxylase
converts arachidonic acid to 20-HETE in Cyp 4 pathway (smooth muscle)
Epoxygenase
converts arachidonic acid to EETs in Cyp 2 pathway (astrocytes)
sEH
enzyme that degrades EETs
PLA2, COX1 and COX2 all prefer _____
omega 6’s over omega 3
Which are neutral to omega 3 or omega 6?
phospholipid synthesis enzymes and linear and cytochrome 450 pathways
How can a diet high in omega-6 lead to obesity? (2 ways)
1) increased phospholipids so increased arachidonic acid –> cyclic pathway –> PGE2 which binds to EP3 receptor which suppresses cAMP production, decreases lipolysis which leads to increased fat accumulation –> obesity
2) phospholipids –> higher AA –> higher 2AG and AEA which binds to cannabinoid receptor and leads to increased food intake, fat storage and inflammation
PGE2 (and KO)
prostaglandin that is product of cyclic pathway, KO of PGE2 causes decreased adiposity (increased lipolysis and FAO)
CB1R
Cannabinoid receptor
2AG and AEA
increase appetite, increase fat storage/obesity and inflammation, decrease fatty acid oxidation (bind to cannabinoid receptor)
Caloric restriction
undernutrition without malnutrition (reduced calories, adequate nutrients) and seems to lead to increased health span
Benefits of caloric restriction
Decreased blood glucose and insulin levels, decreased risk of insulin resistance/diabetes, heart disease and cancer, decreased oxidative damage and inflammation…
Negative effects of caloric restriction
Increased hunger, erratic temperament, decreased libido, decreased bone and muscle density, immunosuppression
AMPK
sensor of low energy that promotes glucose transport, fatty acid oxidation
mTOR
stimulates translation - regulates growth and cell division
Sirtuins
genes that regulate metabolism and mitochondrial function, stimulated by CR
Sestrins
activate AMPK
IGF-1 signaling
stimulates growth and advances aging, CR antagonizes the IGF receptor
Cell response to CR
cell fitness and longevity: autophagy, stress defense mechanisms while attenuating inflammation and growth
Metformin
activates AMPK so promotes CR-like transcriptional changes
Rapamycin
inhibits mTOR, extends life span in mice only
Resveratrol
activates sirtuin and AMPK - promotes healthy aging
Genetic variant that 95% of celiac patients have
HLA DQ2 or DQ8
Gliadin
Protein fraction of gluten, highly toxic
tissue transglutaminase
converts gliadin into deamidated peptide (even more toxic)
NOD2
gene that when mutated is associated with Crohn’s disease (only 25% of Crohn’s disease patients have mutations)
Triggers of IBD
environment, genetics, intestinal microbiota, immune response irregularities
Crohn’s disease mechanism
normally intestinal microflora trigger NOD2 to trigger NF-kB and defensins are released, however if paneth cells have mutated NOD2, then NF-kB is not triggered and defensins are not released, leading to bacterial overgrowth
Defensins
small peptides that kill bacteria
Treatments for IBD (not celiac disease)
glucocorticoids, free radical scavengers, antibiotics, PXR agonists
PPARalpha
catalyzes fatty acid oxidation, anti-inflammatory
PPARgamma
reduces hyperglycemia and promotes pre-adipocyte differentiation
PPARbeta/delta
anti-inflammatory effects by inhibiting NF-kB
Aerobic glycolysis
Warburg effect - cancer cells switch to less efficient metabolism that results in 4 ATP
Oxidative phosphorylation
Normal metabolism - results in ~36 ATP
Why do cancer cells switch to less efficient metabolism?
They may need other metabolic intermediates more than ATP, nutrients are shifted away from energy metabolism to support cell proliferation
Glucose is used by cancer cells for:
Making acetyl-coA (fatty acids), non essential amino acids, ribose for nucleotides
Lipid metabolism in cancer
Tumor load promotes breakdown of lipids in adipose tissue in cachexia, also stimulates fatty-acid synthesis –> lipids support cell growth, proliferation etc
Reductive carboxylation
glutamine is converted to citrate which can be used to form lipids through reverse TCA cycle
Carcinogenic compunds
heterocyclic amines, nitrosamines and aflatoxin
Chemopreventative compounds
Isoflavones, indoles, polyphenols
Obesity contributes to cancer risk
by increasing insulin secretion and availability of IGF1 due to increased production of IGF binding protein
Hormonally active form of vitamin D aka calcitriol
1,25 dihydroxycholecalciferol
1 alpha hydroxylase
converts vitamin D prohormone into active hormone
Source of vitamin D
diet, sunlight (half life 1 day)
Source of prohormone 25-OH-D
liver (half life 3 weeks) - blood test for this
Source of active hormone 1,25,(OH)2D
kidney (half life 2 hours)
vitamin D prohormone enters cell via
megalin-cubulin mediated endocytosis
vitamin D enters cell via
diffusion
Process by which vitamin D influences immune response
TLR binds a pathogen, TLR increases 1alpha hydroxylase and VDR expression, 25(OH)D enters cell and converted to active form so it can bind to VDR –> VDR transcribes antimicrobial peptides (defensins and hCAP) which target and kill pathogen
Toll-like receptors (TLR)
Pattern recognition receptors which recognize conserved molecular patterns of microbial pathogens
Innate immune response
non-specific immune response with pattern recognition receptors and production of antimicrobial peptides
VDR negatively regulates its own activity by:
increasing production of enzyme that degrades active vitamin D, down regulation of TLR and down regulation of NF-kB
Angiotensinogen
Produced in the liver and acted upon by renin to produce angiotensin 1
Renin
produced in the kidneys and acts upon angiotensinogen
Angiotensin converting enzyme
found in the lungs and converts angiotensin 1 to angiotensin 2
Aldosterone
converted from angiotensin 2 in the adrenals, acts on heart to increase heart rate and on blood vessels - vasoconstriction - both increase blood pressure.. also signals kidneys to retain water and sodium
ANP
opposite effect of aldosterone, lowers blood pressure
MR (mineralocorticoid receptor)
receptor for aldosterone (which is the main mineralocorticoid - steroid hormone that influences salt and water balance)
AT1R
main receptor in RAAS
