Bile acids are the major transporters of fat products in the intestine.  They

• form mixed micelles with the fat products 
  • phospholipids, lysolecithin, FFAs, cholesterol, 2-MG, Vit A/D/E/K
• in order to solubilize them
• in order to transport them to intestinal cells for absorption

CCK is stimulated by 

• Release of chyme and FFAs into duodenal lumen (fat digestion)
• Release of AAs into duodenal lumen (protein digestion)

CCK once secreted by the intestine goes to 2 locations

• Intestinal lumen
• Blood→pancreas, gallbladder

In the PANCREAS, CCK stimulates release of fat-digesting hormones, protein-digesting hormones and bicarb:

• Trypsinogen
• Procolipase
• Lipase
• Esterase
• Pro-PLA₂
• _{Chymotrypsinogen (protein-digesting)}
• _{Proelastase (protein-digesting)}
• _{Procarboxypeptidase (protein-digesting)}
• HCO3- (neutralizes acid so enzymes can work)

In the INTESTINE, CCK stimulates secretion of 

• Enteropeptidase
  • Trypsinogen→Trypsin (causes activation of pancreatic zymogens in intestine)

1. RBP = retinol (blood transport)
2. CRBP = retinol (cytoplasm)
3. CRABP = retinoic acid (produced in epithelial cells)

1. Retinal = vision
2. Retinol = gonads
3. Retinol palmitate = storage form in liver
4. Retinoic acid = embryonic development, epithelial cell growth/differentiation

Decreased

Glutamate

Gt

Close

Hyperpolarize

Decrease

Rhodopsin kinase (for cessation)

Arrestin (for complete inactivation ~ prevents dephoshoprylation)

Rhodopsin

Metarhodopsin II

Embryo (neural crest = craniofacial, cardiac, CNS/PNS)

Eye (night vision, keratinization of lens)

Infection (keratinization of skin/GI/GU/lungs→ cracking→ infection)

Endocrine = ductless glands

Exocrine = glands that secrete into ducts

1) Intracellular = go into cell and exert effects on genes

2) Extracellular = exert effects via 2nd messenger systems

1) Neural = hypothalamohypophyseal tract

2) Humoral = hypophyseal portal system.  Neuronal axons terminate in the median eminence, a site lacking the BBB, so hormones leak into here, which carries hormones via the portal plexus system to the anterior pituitary.

• Adenohypophysis (oral ectoderm invagination = Rathke's pouch)
  • Pars distalis (big pouch)
  • Pars intermedia (intermediate)
  • Pars tuberalis (stalk)
• Neurohypophysis (neuroectoderm)
  • Pars nervosa
  • Pars infundibulum

Neurohypophysis

• Neurons (axons)
• Pituicytes (neuroglia)

• Somatotrophs (GH, STH, somatotropin)
• Mammotrophs (Prolactin)
• Gonadotrophs (LH, FSH)
• Thyrotrophs (TSH)
• Corticotrophs (ACTH)

• Pinealocytes
• Interstitial cells (astrocyte-like)

Neurohypophysis =

• ADH = kidney
• OT = uterus, breast

Adenohypophysis = 

• GH, Somatotropin, STH = bone growth
• Prolactin = mammary glands
• LH = ovaries, testicular IC cells
• FSH = follicles, spermatogenesis
• TSH = thyroid
• ACTH = adrenal cortex

Melatonin

Serotonin

Anatomic = the pineal gland's neural input is from the superior cervical ganglion (visual system).  

Physiologic = visual input INHIBITS melatonin release.  Thus, greater amounts of melatonin are released at night.  

Thyroid

• T3, T4
• Calcitonin

Parathyroid

• PTH

Thyroid = Osteoclast (inhibition), via Calcitonin

Parathyroid = Osteoclast (stimulation), via PTH

• Goiter
• Exophthalmos
• Dermatopathy
  • Pre-tibial myxedema = scaly skin on shins

Wolff-Chaikoff effect--Iodide trapping is inhibited when blood iodide is high.  

1. Peroxidase
2. Thyroid-specific deiodinase

Thyroid hormones are the most sluggish of the hormones; plus the circadian rhythms only affect the hypothalamo-pituitary axis--so, T3/T4 levels tend to dampen the diurnal rhythm obvious in TSH levels.

1. TBG = 70%; hi-affinity, low-capacity
2. Albumin = 20%; low-affinity, high-capacity
3. TBPA/Transthyretin = 10%; intermediate

It's significant because only the unbound form of thyroid hormone is available for affecting cells.

The body deals with an increase in the amount of thyroid binding proteins (eg, in pregnancy!!!) by:

1. Decreasing excretion rate 
2. Increasing production rate

NET protein use→muscle wasting, wt. loss, weakness

• Med concentrations = increased synthesis
• Hi concentrations = increased breakdown

NET lipolysis

• (TG, CE synthesis also increased)

CATABOLIC = glycogenolysis, gluconeogenesis, glucose oxidation.

On GLUCOSE:

• Increased GI absorption
• Increased peripheral uptake (by insulin)

1. Heart = increased BP/HR, etc.
   • Upregulates Beta-1 receptors (not amount of catecholamines!!)
2. CNS = development
   • Path = cretinism = severe irreversible mental retardation
3. Skeleton = maturation

1. Calorigenic effect = energy metabolism, heat production 
   • via increased Na/K ATPase

Oxidative enzymes (G3PDH)
Mitochondrial UCP

Na/K ATPase

Growth hormone

Beta-1 receptors

Mineral

Collagen

Cells

Osteoporosis = decreased overall bone mass (collagen, mineral, cells)

Osteomalacia/Rickets = decreased bone mineral

von Recklinghausen's = hyperparathyroidism-induced decreased bone mineral with increased cysts (decalcification, cystic brown tumor lesions with fibrosis)

Osteoporosis = decreased estrogen→increased OCs, decreased OBs

Osteomalacia = decreased Vitamin D (adults)→hypocalcemia→increased PTH→increased OCs

Rickets = decreased Vitamin D (children)→hypocalcemia→increased PTH→increased OCs

von Recklinghausen's = increased PTH→increased OCs

Similiarity = both caused by Vitamin D deficiency

Difference = 

• Osteomalacia = ↓ Vitamin D in mature bone (adults)
• Rickets = ↓ Vitamin D in growing bone (kids)

Osteomalacia = vitamin D absorption/metabolism problems, so:

• chronic renal failure
• Malabsorption 

• Decreased intake = due to decreased nutrition/sunlight (nutritional rickets)
• Decreased production = 1-OHase defect (Type 1 HVDRR)
• Decreased cell uptake = Vitamin D receptor defect (Type 2 HVDRR)
  • DNA-binding domain
  • Hormone binding domain

Type 1 HVDRR = Yes

Type 2 HVDRR = 

• DNA-binding domain = NO
• Hormone-binding domain = Yes

HVDRR 1 = high 25(OH)D₃, low 1,25(OH)₂D₃

HVDRR 2 = high 1,25(OH)₂D₃ 

• Senile = old people.  Due to aging (decreased OBs).
• Post-menopausal = women.  Due to decreased estrogen (increased OC activity, decreased OB activity)

1. Hip
2. Radius
3. Vertebrae

Normal =  (note normal thickness of osteoid)

http://content.edgar-online.com/edgar_conv_img/2005/12/21/0000950134-05-023569_A15650A1565002.GIF

Osteomalacia = widened osteoid seams

 http://www.scielo.br/img/revistas/abem/v54n2/02f2.jpg

C = Carcinoma

H = HHM

I = Intoxication of Vitamin D, immobilization

M = Milk-alkali syndrome, 

P = Paget's disease

S = Sarcoidosis

• PTH = 
  • Low supply = hypoparathyroidism
  • End-organ resistance = pseudohypoparathyroidism
• Vitamin D
  • Low supply = rickets, Type 1 HVDRR
  • End-organ resistance = Type 2 HVDRR

• Primary = increased tissue
  • Adenoma, Hyperplasia, Carcinoma
• Secondary = ↓ Ca→↑ PTH
  • Renal disease, Malabsorption
• Tertiary = long-standing ↓ Ca→↑ PTH→ autologous PTH secretion
  • Chronic renal disease

• 95% of primary hyperparathyroidism is sporadic
• 5% of primary hyperparathyroidism is familial = MEN-1, MEN-2, FHH
  • MEN-1 = most.  loss of MEN-1 gene from chromosome 11q13
  • MEN-2 = activating mutation of RET proto-oncogene (TYK receptor) on chromosome 10q.
• Adenomas
  • PRAD1 gene defect coding for cyclin D1 (tumor suppressor)

Cause = resistance to Calcium receptor (CaR)

S/S = hypercalcemia, hypOcalciuria!

• Hypocalciuria because calcium reabsorption in the kidneys is not feedback-inhibited.

• Cause = PTHrP binds to PTH receptors on bone and acts just like PTH, but is NOT feedback-inhibited.  
• Effect = hypercalcemia

• Adenoma = solitary (usually).  Thin wispy capsule.  No fat.  Lower glands especially!!!
  • MUST bx all glands to distinguish between adenoma vs. hyperplasia.
• Hyperplasia = all glands (usually).  chief cell hyperplasia. 
• Carcinoma = vascular invasion + capsule invasion!

• PTH G protein mutation→end-organ resistance
• Labs = hypocalcemia, hyperphosphatemia.
• (PTH injection→no change in these labs or in urinary cAMP) 

• Primary hyperparathyroidism
  • High PTH
  • High Ca
• Malignancy & hypercalcemia
  • Low PTH
  • High Ca
• Hypoparathyroidism
  • Low PTH
  • Low Ca
• Chronic renal failure
  • High PTH
  • Normal Ca

Stones & bones...

• Bone disease = mild decalcification - osteoporosis
• Renal stones
• GI abnormalities = ulcers, pancreatitis, gallstones
• Metastatic calcifications = leads to CRF if in kidney 
  • In gastric mucosa, kidney, lungs, systemic arteries, pulm veins
• von Recklinghausen disease of bone = late-stage hyperparathyroidism.  General bone decalcification + osteitis fibrosa cystica + multiple fx + renal stones
  • Osteitis fibrosa cystica = fibrosis + cysts (X-ray) + brown tumors (hemorrhage) + lots multi-nucleated OCs

• Catecholamine synthesis (L-dopa→Dopamine)
• Transaminase reactions

• alpha-1 receptor = increased liver glycogenolysis
• beta-2 = more comprehensive:
  • increased liver/muscle glycogenolysis
  • increased gluconeogenesis
  • decreased glycogenesis

• alpha-2 receptor = decreased lipolysis
• beta-2 receptor = increased lipolysis

• Alpha-2 receptor = decreased insulin, glucagon
• Beta-2 receptor = increased insulin, glucagon

• Beta-2 receptors are activated by Epi only.
• Beta-2 receptors are NOT innervated by sympathetic nerves.
• Beta-2 receptors are located on bronchial smooth muscle and skeletal muscle.  
• Thus, Epi can cause vasodilation in certain tissues while NE/Epi cause vasoconstriction in other vessels.

Epi has higher affinity for beta-2 receptors>alpha-2 receptors.

At low doses, Epi decreases blood pressure.  

At high doses, Epi increases blood pressure.

Urinary catecholamines, metanephrine.

Plasma metanephrine.

Alpha-1 agonist = phenylephrine

Alpha-1 antagonist = phenoxybenzamine (pheochromocytoma Tx)

Beta-1 agonist = dobutamine

Beta-2 agonist = albuterol

Beta antagonists = olol's 

Facilitated diffusion in:

1. Small intestine (blood side)
2. Pancreas (blood side)
3. Liver (blood side)

Lumen side:

1. SGLT-2 (sodium-glucose transporter) = active transport/Na+ cotransporter
2. GLUT-5 

1. GLUT-2 (facilitated diffusion)