Biochemistry of special situations Alice Skoumalová

Obesity 1.Structure and function of the insulin receptor. 2.What does “the insulin resistance“ mean? Consequences. 3.How does insulin influence the metabolism of sugars and lipids ? 4.What are the types of lipoproteins? In which tissues are they synthetized? Their composition and function. 5.The fate of the VLDL lipoproteins.

Insulin receptor signaling:  the tyrosine kinase activity  a dimer (α and ß subunits) Signal transduction: 1. the ß-subunits autophosphorylate each other when insulin binds (activating the receptor) 2. the activated receptor binds and phosphorylates IRS (insulin receptor substrate) 3. multiple binding sites for different proteins

Binding of insulin to its cell membrane receptor causes vesicles containing glucose transport proteins to move from inside the cell to the cell membrane Stimulation by insulin of glucose transport into muscle and adipose cells:

Pathways affected by insulin 1. Carbohydrate metabolism stimulation of glucose utilization: glycogen synthase ↑ glycolysis ↑ inhibition of gluconeogenesis the transport of glucose into tissues (muscle, adipose tissue) 2. Lipid metabolism stimulation of the glucose conversion into FA: acetyl CoA carboxylase ↑ NADPH (PPP ↑) storage of fat: lipoprotein lipase ↑ inhibition of the degradation of fat: hormone sensitive lipase ↓

Lipoproteins Function:  Lipid transport (cholesterol, cholesterol esters, triacylglycerols, phospholipids) Structure: A nucleus: triacylglycerols, cholesterol esters A shell: phospholipids, apoproteins, cholesterol

Characteristics of the major lipoproteins LipoproteinOriginHalftime in blood Major apoproteins Major lipids Function Chylomicronsintestine5-15 minB-48, C-II, ETGDeliver dietary lipids VLDLliver2hB-100, E, C-IITGDeliver endogenous lipids IDLplasm2hB-100, E, C-IITG/CHEPrecursor of LDL LDLplasm2-4 dnyB-100CHEDeliver cholesterol to cells HDL (nascent) liver, intestine, plasm 10h ?A-I, C-II, EPL/CHEReverse cholesterol transport

Composition of lipoproteins

Metabolism of VLDL, IDL and LDL

Obesity Epidemiology: BMI:25-30 kg/m 2 - overweight > 30 kg/m 2 - obesity Causes:  dysbalance between the energy input and output( + genetic predispositions)  (endocrine disorders-hypothyroidism, Cushing´s disease)  (mutations) Health consequences: DM type 2, hypertension, dyslipidemia, cardiovascular diseases, certain carcinomas

Genetics  40-70% (polygenic)  monogenic (e.g. leptin) Peptides influencing „appetite“: 1.Central (neuropeptide Y, melanocortines, serotonin) 2.Peripheral (cholecystokinine, peptide YY, pancreatic polypeptide, leptin)

Consequences of obesity → Metabolic syndrom: 1.Obesity (abdominal) 1.↑ leptin, resistin, TNFα 2. ↓ adiponectin 2.Insulin resistance  ↑ FFA in blood, inhibition of glucose utilization, inhibition of GLU4  dysfunction of the inzulin receptor (e.g. by TNF α )  reduced prodution of adiponectin 3.Dyslipidemia (nonenzymatic glycation of apolipoproteins, ↑ lipolysis, dysfunction of LPL, dysfunction of LDL receptors) 4.Hypertension (stimulation of sympathetic nervous system, retention of Na + and vasoconstriction as a result of hyperinsulinemia) DeFronzo et al. Diabetes Care 1992; 15:318

Malnutrition What are the essential amino acids? The major metabolic adaptations to starvation. Describe the Cori cycle ?

Malnutrition Protein malnutrition (kwashiorkor) in children 1-3 years of age protein-poor diet (containg sufficient amount of calories) Symptoms: ↑ insulin  ↓ growth  ↓ proteins and amino acids in plasm, muscle wasting  edema, diarrhea, increased susceptibility to infection  fat stores are maintained Diminished protein synthesis in all tisues, hepatomegaly, dysfunction of the gut (→ malabsorption)

Starvation lack of calories (in developing countries, in patiens with diseases that prevent swallowing) Absence of subcutaneous fat and hepatomegaly (x kwashiorkor) Symptoms: insulin ↓  mobilization of fat stores and muscle proteins  ketone bodies production  reserves exhaustion, death Malnutrition

Cancer cachexia Loss of fat and muscle tissue  increased energy requirements of the tumor  endocrine abnormalities (insulin resistance, ↑ cortizol, ↑BMR) as a result of secretion of certain peptides  production of inflammation peptides by an organism (fever, proteolysis, lipolysis) Tumors function independently of the starve-feed cycle (do not respond to the hormonal changes) Oxidize glucose and amino acids, do not use FA and ketone bodies, establish the Cori cycle Reduced supply of O 2 → hypoxia-inducible factor 1 α (HIF-1 α) → glycolysis

Pregnancy and lactation 1. Nitrogen balance (what does it mean, examples). 2. Urea synthesis, importance, precursors, major steps. 3. The structure of lactose, its synthesis.

Lactose: Metabolism of galactose:

Pregnancy Insulin rezistance (placental steroids) → after a meal↑ Glu and insulin Plasma glucose, amino acids, and insulin level fall rapidly Stimulation of lipolysis (placental lactogen) Glucagon → ketogenesis

Lactation Induction of lipoprotein lipase in the mammary gland (prolactin) Lactose and TG production from glucose Protein synthesis from amino acids Not supplied by the diet: proteolysis, gluconeogenesis, lipolysis (→ maternal malnutrition) Secretion of parathyroid hormone-related protein (PTHrP) → stimulation of the absorption of Ca and P