Pathology (environmental 6)

cabbage, cauliflower, spinach, egg yolk, and liver

• in plants as phylloquinone (or vitamin K1), and in intestinal bacterial flora as menaquinone (or vitamin K2).
• For therapy, a synthetic derivative of vitamin K, menadione

• Formation of γ-carboxyglutamate (Gla)
• Vitamin K is required in the hepatic synthesis of prothrombin and blood clotting factors II, VII, IX, and X.
• These proteins are synthesized as inactive precursor molecules. Formation of the clotting factors requires the vitamin K–dependent carboxylation of glutamic acid residues.
• This forms a mature clotting factor that contains Gla and is capable of subsequent activation. The reaction requires O2, CO2, and the hydroquinone form of vitamin K.
• The formation of Gla is sensitive to inhibition by dicumarol, an anticoagulant occurring naturally in spoiled sweet clover, and by warfarin, a synthetic analog of vitamin K

• The Gla residues of prothrombin are good chelators of positively charged calcium ions, because of the two adjacent, negatively charged carboxylate groups.
• The prothrombin–calcium complex is then able to bind to phospholipids essential for blood clotting on the surface of platelets. Attachment to the platelet increases the rate at which the proteolytic conversion of prothrombin to thrombin can occur

hemolytic anemia and jaundice in the infant, due to toxic effects on the membrane of red blood cells.

• A true vitamin K deficiency is unusual because adequate amounts are generally produced by intestinal bacteria or obtained from the diet.
• Antibiotic in malnourished.
• In addition, certain second-generation cephalosporins, cefoperazone, cefamandole, and moxalactam cause hypoprothrombinemia, apparently by a warfarin-like mechanism.
• Newborns have sterile intestines and so initially lack the bacteria that synthesize vitamin K. Because human milk provides only about one fifth of the daily requirement for vitamin K, it is recommended that all newborns receive a single intramuscular dose of vitamin K as prophylaxis against hemorrhagic disease

The primary function of vitamin E is as an antioxidant in prevention of the nonenzymic oxidation of cell components, for example, polyunsaturated fatty acids, by molecular oxygen and free radicals.

PUFA

Vegetable oils are rich sources of vitamin E, whereas liver and eggs contain moderate amounts

• Vitamin E deficiency is almost entirely restricted to premature infants. When observed in adults, it is usually associated with defective lipid absorption or transport. The signs of human vitamin E deficiency include sensitivity of erythrocytes to peroxide, and the appearance of abnormal cellular membranes
• In childrena and adults ataxia, hyporeflexia, and loss of proprioceptive and vibratory sensation

vitamin K antagonism

• Inadequate supplementation in artificial diet  
• Interference with absorption (zinc therapy, gastrectomy, malabsorption syndromes)

• Fragile, abnormally-formed hair, depigmentation of the skin, muscle weakness (myeloneuropathy), neurological abnormalities, edema, and hepatosplenomegaly, and osteoporosis
• anemia (usually microcytic) and neutropenia

• Zinc-copper superoxide dismutase (antioxidant defense);
• dopamine beta hydroxylase (neurotransmitter synthesis)
• Lysyl oxidase (collagen cross-linking, bone formation)
• Ceruloplasmin (copper transporter and ferroxidase)
• Cytochrome c oxidase (electron transport)
• Factor V (thrombosis)
• Tyrosinase (melanin production)

• X-linked.
• Caused by a mutation of the transport protein mediating copper uptake from the intestine, encoded by the ATP7A gene.
• Inactivating mutations in this gene result in severe copper deficiency with progressive neurologic deterioration and death during early childhood
• The clinical manifestations of Menkes disease are those of copper deficiency, but are severe and occur during early infancy.
• developmental delay,and progressive neurologic symptoms.
• Physical features include peculiar "kinky" hair, growth retardation, hypopigmentation of the skin, and bony abnormalities, including osteoporosis and spur formation

Cr

• Menke (ATP7A)--> reduces the transport of copper from the intestine and internally in other tissues, effectively causing copper malabsorption and maldistribution leading to a copper deficiency state 
• Wilson (ATP7B)--> In Wilson disease, there is decreased incorporation of copper into ceruloplasmin and decreased transport of copper from the liver into bile, leading to copper excess despite low circulating levels of ceruloplasmin (the major form of circulating copper)

zinc

metallothionein

Zinc absorption may be impaired in pancreatic disease or insufficiency. Pancreatic enzymes are necessary for release of dietary zinc, and pancreatic juices may contain zinc-complexing ligands. Phytic acid is known to reduce zinc absorption. Zinc shares some common absorptive components with iron and copper, and the three minerals may compete for absorption.

ACE, ALK, carbonic anhydrase, DNA and RNA polymerases, copper-zinc SOOD, and metallothionein, and oxidases as well as a large family of zinc proteins involved in gene transcription (such as the zinc finger proteins)

form tight bonds with certain amino acids, especially histidine and cysteine

• When zinc binds four amino acids (tetradentate configuration), it serves a structural role maintaining protein structure (such as the beta-pleated sheet), and maintains nuclear stability and histone structure. It is in this form that zinc contributes to zinc finger proteins that interact with DNA.
• When zinc binds three amino acids, the fourth site is temporarily taken by a water molecule; in this form, zinc can play a role in the metabolic activity of many proteins

• Rash around eyes, mouth, nose, and anus called acrodermatitis enteropathica  
• Anorexia and diarrhea  
• Growth retardation in children  
• Depressed mental function  
• Depressed wound healing and immune response  
• Impaired night vision  
• Infertility
• Loss of taste

• AR
• zinc transporter
• diarrhea, dermatitis (especially perioral and perianal), alopecia, poor growth, and poor immune function.
• The dermatitis consists of hyperpigmented skin lesions on the acral surfaces of the upper and the lower extremities, as well as the face and buttocks.
• Symptoms usually appear in early infancy, once breast-feeding is completely discontinued.
• Systemic signs include intestinal disturbances, growth failure, irritability, and lethargy

• Component of glutathione peroxidase  
• Antioxidant with vitamin E
• Inadequate amounts in soil and water  
• Myopathy  Cardiomyopathy (Keshan disease)

• Thiamine: yeast, legumes, pork, rice, and cereals (not milk or fruit and vegetables)
• Riboflavin: Many meats, fish, eggs and milk, green vegetables
• Niacin: many yeast, meats (especially liver), cereals, legumes, and seeds
• B6: Meats, whole grains, vegetables, and nuts 
• Vitamin C: citrus fruits, tomatoes, potatoes, brussel sprouts, cauliflower, broccoli, strawberries, cabbage, and spinach
• Vitamin A: liver, kidney, egg yolk, and butter. Provitamin A (beta-carotene) is mostly found in green leafy vegetables, sweet potato and carrots.
• Vitamin D: UV/ fortified milk, fatty fish, cod-liver oil
• Vitamin E: vegetable oils, meat, eggs, and leafy vegetables
• Vitamin K: gut flora, green vegetables like spinach and broccoli
• B12: Animal products
• B9: animal products and in leafy vegetables (eg, green leafy vegetables, fruits, cereals and grains, nuts, and meats) in the polyglutamate form 

• Nutritional niacin def
• Carcinoid
• HArtnup (abnormal tryptophan transport)
• Prolonged use of isoniazid (isoniazid depletes stores of pyridoxal phosphate, which enhances the production of tryptophan, a precursor of niacin)

The normal BMI range is 18.5 to 25 kg/m2, although the range may differ for different countries. Individuals with BMI above 30 kg/m2 are classified as obese; those with BMI between 25 kg/m2 and 30 kg/m2 are considered to be overweight

Accumulation of body fat may also be measured by triceps skinfold thickness, mid-arm circumference, and the ratio between waist and hip circumferences

Central, or visceral, obesity, in which fat accumulates in the trunk and in the abdominal cavity (in the mesentery and around viscera), is associated with a much higher risk for several diseases than is excess accumulation of fat diffusely in subcutaneous tissue

Hypothalamus

• The peripheral or afferent system generates signals from various sites. Its main components are leptin and adiponectin produced by fat cells, ghrelin from the stomach,peptide YY (PYY) from the ileum and colon, and insulin from the pancreas.  
• The arcuate nucleus in the hypothalamus processes and integrates neurohumoral peripheral signals and generates efferent signals. It contains two subsets of first-order neurons: (1) POMC (pro-opiomelanocortin) and CART (cocaine and amphetamine-regulated transcripts) neurons, and (2) neurons containing NPY (neuropeptide Y) and AgRP (agouti-related peptide). These first order neurons communicate with second order neurons. 
• The efferent system that carries the signals generated in the second order neurons of the hypothalamus to control food intake and energy expenditure. The hypothalamic system also communicates with forebrain and midbrain centers that control the autonomic nervous system

Arcuate nucleus of hypothalamus

• POMC/CART neurons enhance energy expenditure and weight loss through the production of the anorexigenic α-melanocyte-stimulating hormone (MSH), and the activation of the melanocortin receptors 3 and 4 (MC3/4R) in second-order neurons.
• NPY/AgRP neurons promote food intake (orexigenic effect) and weight gain, through the activation of Y1/5 receptors in secondary neurons

• Leptin, a 16-kD hormone synthesized by fat cells, is the product of the ob gene.
• The leptin receptor (OB-R) is the product of the diabetes (db) gene and belongs to the type I cytokine receptor superfamily.
• Mice genetically deficient in leptin (ob/ob mice) or leptin receptors (db/db mice) fail to sense the adequacy of fat stores, overeat, and gain weight, behaving as if they are undernourished.
• Thus, the obesity of these animals is a consequence of the lack of the signal for energy sufficiency that is normally provided by leptin

fail to sense the adequacy of fat stores, overeat, and gain weight, behaving as if they are undernourished

• adequacy of fat stores
• Leptin levels are regulated by multiple post-transcriptional mechanisms that affect its synthesis, secretion, and turnover.

When adipose stores are abundant

• In the hypothalamus, leptin stimulates POMC/CART neurons that produce anorexigenic neuropeptides (primarily MSH) and inhibits NPY/AgRP neurons that produce feeding-inducing (orexigenic) neuropeptides.
• In individuals with stable weight, the activities of the opposing POMC/CART and NPY/AgRP pathways are properly balanced.
• However, when there are inadequate stores of body fat, leptin secretion is diminished and food intake is increased

• Leptin--> stimulate POMC/CART (MSH), inhibit NPY/AgRP(NPY)
• Ghrelin--> stimulate NPY/AgRP (NPY)
• Pyy--> inhibit NPY/AgRP(NPY)

• melanocortin receptor 4 (MC4R)
• In these individuals, sensing of satiety (anorexigenic signal) is not generated, and hence they behave as if they are undernourished

True

• An abundance of leptin stimulates physical activity, heat production, and energy expenditure.
• Thermogenesis, an important catabolic effect mediated by leptin, is controlled in part by hypothalamic signals that increase the release of norepinephrine from sympathetic nerve endings in adipose tissue.
• In addition to these effects, leptin can function as a pro-inflammatory cytokine and participates in the regulation of hematopoiesis and lymphopoiesis.
• The OB-R receptor is highly similar structurally to the IL-6 receptor and activates the JAK/STAT pathway

JAK/STAT pathway

Adiponectin

• Injections of adiponectin in mice stimulate fatty acid oxidation in muscle, causing a decrease in fat mass.
• This hormone is produced mainly by adipocytes.
• Its levels in the blood are very high and are lower in obese than in lean individuals.
• Adiponectin directs fatty acids to muscle for their oxidation.
• It decreases the influx of fatty acids to the liver and the total hepatic triglyceride content, and also decreases the glucose production in the liver, causing an increase in insulin sensitivity and a protection against the metabolic syndrome 
• Adiponectin circulates as a complex of three, six, or even more aggregates of the monomeric form, and binds to two receptors, AdipoR1 and AdipoR2.
• These receptors are found in many tissues, including the brain, but AdipoR1 and AdipoR2 are most highly expressed in skeletal muscle and liver, respectively.
• Binding of adiponectin to its receptors triggers signals that activate cyclic adenosine monophosphate–activated protein kinase, which in turn phosphorylates and inactivates acetyl coenzyme A carboxylase, a key enzyme required for fatty acid synthesis.

• Inhibit AcoA carboxylase and thus FA synthesis
• Enhance beta oxidation of FA in muscle
• Enhance insulin sensitivity

• In addition to leptin and adiponectin, adipose tissue produces cytokines such as TNF, IL-6, IL-1, and IL-18, chemokines, and steroid hormones.
• The increased production of cytokines and chemokines by adipose tissue in obese patients creates a chronic sub-clinical (asymptomatic) inflammatory state that includes high levels of circulating C-reactive protein

• The total number of adipocytes is established during childhood and adolescence, and it is higher in obese than in lean individuals.
• In adults the number of adipocytes remains constant, even after losses or weight gains, but there is a continuous turnover of the cell population.
• 10% of adipocytes are renewed annually, regardless of the level of the individual's body mass.
• Thus, although the fat mass in an adult person can increase through the enlargement of existing adipocytes, their number is tightly controlled, and is predetermined in childhood and adolescence.
• In individuals who lose weight after dietary regimens, the well-known difficulties in maintaining weight losses are, in part, a consequence of the lack of a decrease in the number of adipocytes, and the enhanced appetite caused by leptin deficiency

Ghrelin

• Ghrelin is produced in the stomach and in the arcuate nucleus of the hypothalamus. 
• It is the only known gut hormone that increases food intake (orexigenic effect).
• Its injection in rodents elicits voracious feeding, even after repeated administration. Long-term injections cause weight gain, by increasing caloric intake and reducing energy utilization.
• Ghrelin acts by binding the growth hormone secretagogue receptor, which is abundant in the hypothalamus and the pituitary.
• It stimulates NPY/AgRP neurons to increase food intake.
• Ghrelin levels rise before meals and fall between 1 and 2 hours after eating. However, in obese individuals the postprandial suppression of ghrelin is attenuated, leading to maintenance of the obesity

However, in obese individuals the postprandial suppression of ghrelin is attenuated, leading to maintenance of the obesity

• PYY is secreted from endocrine cells in the ileum and colon.
• Plasma levels of PYY are low during fasting and increase shortly after food intake.
• Intravenous administration of PYY reduces energy intake, and its levels generally increase after gastric bypass surgery.
• By contrast, levels of PYY generally decrease in individuals with the Prader-Willi syndrome(caused by loss of imprinted genes on chromosome 15q11–q13), and may contribute to the development of hyperphagia and obesity in these persons.
• Amylin, a peptide secreted with insulin from pancreatic β-cells that reduces food intake and weight gain, is also being evaluated for the treatment of obesity and diabetes.
• Both PYY and amylin act centrally by stimulating POMC/CART neurons in the hypothalamus, causing a decrease in food intake

• DM2
• Metabolic syndrome, HTN
• hypertriglyceridemia and low HDL
• Insulin resistance
• Cholelithiasis 
• NAFLD
• hypoventilation and hypersomnolence
• OA
• In men adenocarcinoma of the esophagus, and cancers of the thyroid, colon, and kidney
• In women adenocarcinoma of the esophagus, and of endometrial, gallbladder, and kidney cancers.

insulin, may play a role in the retention of sodium, expansion of blood volume, production of excess norepinephrine, and smooth muscle proliferation that are the hallmarks of hypertension

association between obesity and heart disease is not straightforward, and such linkage as there may be relates more to the associated diabetes and hypertension than to weight

An increase in total body cholesterol, increased cholesterol turnover, and augmented biliary excretion of cholesterol all act to predispose to the formation of cholesterol-rich gallstones

Adiponectin

• 1.   In men, a BMI greater than 25 kg/m2 correlated strongly with an increased incidence of adenocarcinoma of the esophagus, and cancers of the thyroid, colon, and kidney.  
• 2.   In women, a BMI greater than 25 kg/m2 correlated strongly with an increased incidence of adenocarcinoma of the esophagus, and of endometrial, gallbladder, and kidney cancers.

• increased cancer risk in obese individuals is a consequence of hyperinsulinemia and insulin resistance 
• Insulin at high concentrations has multiple effects on cell growth, including the activation of phosphatidylinositol 3-kinase, extracellular-signal-regulated kinases 1 and 2, β-catenin, and Ras.
• Hyperinsulinemia also causes an increase in IGF-1 concentrations, because insulin inhibits the production of the IGFBP-1 and IGFBP-2.
• IGF-1 is a mitogenic and anti-apoptotic agent that is highly expressed in many human cancers. It binds with high affinity to the IGF-1R receptor, and with low affinity to the insulin receptor. IGF-1 activates many of the cell growth pathways that are also activated by insulin, and increases the production of VEGF, by inducing the expression of HIF1.
• In addition to the obesity-associated effects of insulin and IGF-1 in cell growth pathways, obesity and hyperinsulimia have an effect on steroid hormones that regulate cell growth and differentiation in the breast, uterus, and other tissues: (1) obesity increases the synthesis of estrogen from androgen precursors through an effect of adipose tissue aromatases; (2) insulin increases androgen synthesis in ovaries and adrenals, and enhances estrogen availability in obese persons by inhibiting the production of sex-hormone-binding globulin (SHBG) in the liver

Gastric cancer

• These compounds can be formed in the body from nitrites and amines or amides derived from digested proteins.
• Sources of nitrites include sodium nitrite added to foods as a preservative, and nitrates, present in common vegetables, which are reduced in the gut by bacterial flora

colon cancer

• high fat intake increases the level of bile acids in the gut, which in turn modifies intestinal flora, favoring the growth of microaerophilic bacteria.
• Bile acid metabolites produced by these bacteria may function as carcinogens

The protective effect of a high-fiber diet might relate to (1) increased stool bulk and decreased transit time, which decreases the exposure of mucosa to putative offenders, and (2) the capacity of certain fibers to bind carcinogens and thereby protect the mucosa

strong positive correlation (but not causation) between total dietary fat intake and breast cancer

A better strategy is to simply focus on eating an enjoyable and healthy diet rich in fish, vegetables, whole grains, fruits, olive and peanut oils (to replace saturated and trans fats), complex carbohydrates (instead of simple carbohydrates contained in sweets and soft drinks), and low in salt (to control hypertension).

vitamin A

Vitamin K or C

niacin

Vitamin B2,3,6

B2 (riboflavin)

Vitamin A

Vitamin B2,6 def

niacin deficiency

vitamin C def

B2,3,6,9,12 def

• B2 deficiency
• purplish red coloration of the tongue, with edema and flattening of the filiform papillae

B1,12 def

• The absorptive state is the two- to four-hour period after ingestion of a normal meal.
• During this interval, transient increases in plasma glucose, amino acids, and triacylglycerols (TAG) occur, the latter primarily as components of chylomicrons synthesized by the intestinal mucosal cells.
• Islet tissue of the pancreas responds to the elevated levels of glucose and amino acids with an increased secretion of insulin and a drop in the release of glucagon.
• The elevated insulin to glucagon ratio and the ready availability of circulating substrates make the absorptive state into an anabolic period characterized by increased synthesis of TAG and glycogen to replenish fuel stores, and enhanced synthesis of protein.
• During this absorptive period, virtually all tissues use glucose as a fuel, and the metabolic response of the body is dominated by alterations in the metabolism of liver, adipose tissue, muscle, and brain.

• The flow of intermediates through metabolic pathways is controlled by four mechanisms:
• 1) the availability of substrates (min);
• 2) allosteric regulation of enzymes (min);
• 3) covalent modification of enzymes( min to hours); and
• 4) induction-repression of enzyme synthesis (hours to days)

• Allosteric changes usually involve rate-determining reactions.  
• Glycolysis in the liver is stimulated following a meal by an increase in fructose 2,6-bisphosphate—an allosteric activator of phosphofructokinase-1.
• Gluconeogenesis is inhibited by fructose 2,6-bisphosphate, an inhibitor of fructose 1,6-bisphosphatase

• Many enzymes are regulated by the addition or removal of phosphate groups from specific serine, threonine, or tyrosine residues of the enzyme.
• In the fed state, most of the enzymes regulated by these covalent modifications are in the dephosphorylated form and are active.
• Three exceptions are glycogen phosphorylase kinase, glycogen phosphorylase, and hormone-sensitive lipase of adipose tissue, which are inactive in their dephosphorylated state

Induction and repression of enzyme synthesis

• Increased (induction of) or decreased (repression of) protein synthesis leads to changes in the total population of active sites, rather than influencing the efficiency of existing enzyme molecules.
• Enzymes subject to regulation of synthesis are often those that are needed at only one stage of development or under selected physiologic conditions.
• For example, in the fed state, elevated insulin levels result in an increase in the synthesis of key enzymes, such as acetyl coenzyme (CoA) carboxylase and HMG-CoA reductase involved in anabolic metabolism

• Carbohydrate: Increased phosphorylation of glucose/ Increased glycogen synthesis/Increased activity of the hexose monophosphate pathway (HMP)/ Increased glycolysis/Decreased gluconeogenesis
• Fat: Increased fatty acid synthesis/ Increased TAG synthesis
• Aminoacid: Increased amino acid degradation/ Increased protein synthesis

• Carbohydrate: Increased glucose transport/ Increased glycolysis/ Increased activity in the HMP
• Fat: Increased synthesis of fatty acids/Increased TAG synthesis/ Decreased TAG degradation

• Carbohydrate: Increased glucose transport/ Increased glycogen synthesis
• Fat: None
• Aminoacid: Increased protein synthesis/ Increased uptake of branched-chain amino acids

• Carbohydrate: glucose is used as a sole fuel
• Fat: FA does not cross BBB

• This increased use of glucose is not a result of stimulated glucose transport into the hepatocyte, because this process is normally rapid and GLUT-2 is not influenced by insulin.
• Rather, hepatic metabolism of glucose is increased

• Increased phosphorylation of glucose by glukokinase (not subject to inhibition) due to increased availability of glucose
• Increased glycogen synthesis (activation of glycogen synthase—both by dephosphorylation and by increased availability of glucose 6-phosphate, its allosteric effector)
• Increased activity of the hexose monophosphate pathway (HMP) due to The increased availability of glucose 6-phosphate in the well fed state, combined with the active use of NADPH in hepatic lipogenesis
• Increased glycolysis (only in high-carb meal): The conversion of glucose to acetyl CoA is stimulated by the elevated insulin to glucagon ratio that results in increased activity (and amount) of the rate-limiting enzymes of glycolysis, for example, phosphofructokinase
• Decreased gluconeogenesis: Pyruvate carboxylase, which catalyzes the first step in gluconeogenesis, is largely inactive due to low levels of acetyl CoA—an allosteric effector essential for enzyme activity. Note: The acetyl CoA is being used for fatty acid synthesis. The high insulin to glucagon ratio observed in the absorptive period also favors inactivation of other enzymes unique to gluconeogenesis, such as fructose 1,6-bisphosphatase

• Elevated levels of intracellular glucose in the hepatocyte (as a result of elevated extra-cellular levels) allow glucokinase to phosphorylate glucose to glucose 6-phosphate
• This contrasts with the postabsorptive state in which hepatic glucose levels are lower andglucokinase is largely dormant because of its low affinity (high Km) for glucose

The conversion of glucose 6-phosphate to glycogen is favored by the activation of glycogen synthase—both by dephosphorylation and by increased availability of glucose 6-phosphate, its allosteric effector

The increased availability of glucose 6-phosphate in the well fed state, combined with the active use of NADPH in hepatic lipogenesis, stimulate the HMP

• 1) In liver, glycolytic metabolism of glucose is significant only during the absorptive period following a carbohydrate-rich meal.
• 2) The conversion of glucose to acetyl CoA is stimulated by the elevated insulin to glucagon ratio that results in increased activity (and amount) of the rate-limiting enzymes of glycolysis, for example, phosphofructokinase 
• 3) [Note:  Pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl CoA, is active (dephosphorylated) because pyruvate inhibits PDH kinase.
• 4) Acetyl CoA is used as either a building block for fatty acid synthesis, or it provides energy by oxidation in the tricarboxylic acid (TCA) cycle

• Whereas glycolysis is stimulated in the absorptive state, gluconeogenesis is decreased.
• Pyruvate carboxylase, which catalyzes the first step in gluconeogenesis, is largely inactive due to low levels of acetyl CoA—an allosteric effector essential for enzyme activity. [Note: The acetyl CoA is being used for fatty acid synthesis.]
• The high insulin to glucagon ratio observed in the absorptive period also favors inactivation of other enzymes unique to gluconeogenesis, such as fructose 1,6-bisphosphatase

Liver

• Increased fatty acid synthesis: Liver is the primary tissue for de novo synthesis of fatty acids. This pathway occurs in the absorptive period, because dietary caloric intake exceeds energy expenditure by the body. Fatty acid synthesis is favored by the availability of substrates (acetyl CoA and NADPH derived from the metabolism of glucose) and by the activation of acetyl CoA carboxylase, both by dephosphorylation and by the presence of its allosteric activator, citrate. This enzyme catalyzes the formation of malonyl CoA from acetyl CoA—a reaction that is rate-limiting in fatty acid synthesis.
• Increased TAG synthesis: TAG synthesis is favored because fatty acyl CoA is available both from de novo synthesis from acetyl CoA and from hydrolysis of the TAG component of chylomicron remnants removed from the blood by hepatocytes. Glycerol 3-phosphate, the backbone for TAG synthesis, is provided by the glycolytic metabolism of glucose. The liver packages TAGs into very-low-density lipoprotein (VLDL) particles that are secreted into the blood for use by extrahepatic tissues, particularly adipose and muscle tissue 

• Increased amino acid degradation: In the absorptive period, more amino acids are present than the liver can use in the synthesis of proteins and other nitrogen-containing molecules. The surplus amino acids are not stored, but are either released into the blood for all tissues to use in protein synthesis or are deaminated, with the resulting carbon skeletons being degraded by the liver to pyruvate, acetyl CoA, or TCA cycle intermediates. These metabolites can be oxidized for energy or used in fatty acid synthesis. The liver has limited capacity to degrade the branched-chain amino acids leucine, isoleucine, and valine; they pass through the liver essentially unchanged and are preferentially metabolized in muscle.
• Increased protein synthesis: The body cannot store protein in the same way that it maintains glycogen or TAG reserves. However, a transient increase in the synthesis of hepatic proteins does occur in the absorptive state, resulting in replacement of any proteins that may have been degraded during the previous postabsorptive period

• Increased glucose transport: Glucose transport into adipocytes is very sensitive to the concentration of insulin in the blood. Circulating insulin levels are elevated in the absorptive state, resulting in an influx of glucose into adipocytes
• Increased glycolysis: The increased intracellular availability of glucose results in an enhanced rate of glycolysis. In adipose tissue, glycolysis serves a synthetic function by supplying glycerol phosphate for TAG synthesis.
• Increased activity in the HMP: Adipose tissue can metabolize glucose by means of the HMP, thereby producing NADPH, which is essential for fat synthesis. However in humans, de novo synthesis is not a major source of fatty acids in adipose tissue

• Increased synthesis of fatty acids: De novo synthesis of fatty acids from acetyl CoA in adipose tissue is nearly undetectable in humans, except when refeeding a previously fasted individual. Instead, most of the fatty acids added to the lipid stores of adipocytes are provided by dietary fat (in the form of chylomicrons), with a lesser amount is supplied by VLDL from the liver.
• Increased TAG synthesis: After consumption of a lipid-containing meal, hydrolysis of the TAG of chylomicrons (from the intestine) and VLDL (from the liver) provides adipose tissue with fatty acids. These exogenous fatty acids are released by the action of lipoprotein lipase, an extracellular enzyme attached to the capillary walls in many tissues—particularly adipose and muscle. Because adipocytes lack glycerol kinase, glycerol 3-phosphate used in TAG synthesis must come from the metabolism of glucose. Thus, in the well fed state, elevated levels of glucose and insulin favor storage of TAG, all the carbons of which are supplied by glucose.
• Decreased TAG degradation: Elevated insulin favors the dephosphorylated (inactive) state of hormone-sensitive lipase. TAG degradation is thus inhibited in the well-fed state

30/90

Heart muscle differs from skeletal muscle in three important ways: 1) the heart is continuously active, whereas skeletal muscle contracts intermittently on demand; 2) the heart has a completely aerobic metabolism; and 3) the heart contains negligible energy stores, such as glycogen or lipid

• Increased glucose transport: The transient increase in plasma glucose and insulin after a carbohydrate-rich meal leads to an increase in glucose transport into muscle cells. Glucose is phosphorylated to glucose 6-phosphate by hexokinase, and metabolized to provide the energy needs of the cells. This contrasts with the postabsorptive state in which ketone bodies and fatty acids are the major fuels of resting muscle.
• Increased glycogen synthesis: The increased insulin to glucagon ratio and the availability of glucose 6-phosphate favor glycogen synthesis, particularly if glycogen stores have been depleted as a result of exercise.

• Increased protein synthesis: A spurt in amino acid uptake and protein synthesis occurs in the absorptive period after ingestion of a meal containing protein. This synthesis replaces protein degraded since the previous meal.
• Increased uptake of branched-chain amino acids: Muscle is the principal site for degradation of branched-chain amino acids. The branched chain amino acids, leucine, isoleucine, and valine, escape metabolism by the liver, and are taken up by muscle, where they are used for protein synthesis  and as sources of energy

Muscle

2/20

glucose

True

Fed state

• In the absence of food, plasma levels of glucose, amino acids, and TAG fall, triggering a decline in insulin secretion and an increase in glucagon release.
• The decreased insulin to glucagon ratio, and the decreased availability of circulating substrates, makes the period of nutrient deprivation a catabolic period characterized by degradation of TAG, glycogen, and protein.
• This sets into motion an exchange of substrates between liver, adipose tissue, muscle, and brain that is guided by two priorities: 1) the need to maintain adequate plasma levels of glucose to sustain energy metabolism of the brain, red blood cells, and other glucose-requiring tissues, and 2) the need to mobilize fatty acids from adipose tissue, and the synthesis and release of ketone bodies from the liver, to supply energy to all other tissues

• In fasting (as well as in the fed state), the flow of intermediates through the pathways of energy metabolism is controlled by four mechanisms: 1) the availability of substrates, 2) allosteric regulation of enzymes, 3) covalent modification of enzymes, and 4) induction-repression of enzyme synthesis.
• The metabolic changes observed in fasting are generally opposite to those described for the well-fed state.
• For example, most of the enzymes regulated by covalent modification are dephosphorylated and active in the fed state, whereas in the fasted state, they are phosphorylated and active. Three exceptions are glycogen phosphorylase ,glycogen phosphorylase kinase, and hormone-sensitive lipase of adipose tissue, which are inactive in their dephosphorylated states.
• In fasting, substrates are not provided by the diet, but are available from the breakdown of tissues, for example, lipolysis with release of fatty acids and glycerol from adipose tissue, and proteolysis with release of amino acids from muscle.

maintenance of blood glucose through the synthesis and distribution of fuel molecules for use by other organs

• Carbohydrate--> Increased glycogen degradation/Increased gluconeogenesis
• Fat metabolism--> Increased fatty acid oxidation/ Increased synthesis of ketone bodies

• Carbohydrate metabolism-> Glucose transport into the adipocyte and its subsequent metabolism are depressed
• Fat metabolism--> Increased degradation of TAG/ Increased release of fatty acids/ Decreased uptake of fatty acids

• Carbohydrate metabolism--> reduced glucose transport and metabolism
• Lipid metabolism--> During the first two weeks of fasting, muscle uses fatty acids from adipose tissue and ketone bodies from the liver as fuels/ After about three weeks of fasting, muscle decreases its use of ketone bodies and oxidizes fatty acids almost exclusively
• Protein metabolism--> During the first few days of fasting, there is a rapid breakdown of muscle protein/ By several weeks of fasting, the rate of muscle proteolysis decreases

• The liver first uses glycogen degradation and then gluconeogenesis to maintain blood glucose levels to sustain energy metabolism of the brain and other glucose-requiring tissues.
• The presence of glucose 6-phosphatase in the liver allows the production of free glucose both from glycogenolysis and from gluconeogenesis
• Increased glycogen degradation: During the brief absorptive period, glucose from the diet is the major source of blood glucose. Several hours after the meal, blood glucose levels have declined sufficiently to cause increased secretion of glucagon and decreased release of insulin. The increased glucagon to insulin ratio causes a rapid mobilization of liver glycogen stores (which contain about 80 g of glycogen in the well-fed state). Note that liver glycogen is nearly exhausted after 10–18 hours of fasting; therefore, hepatic glycogenolysis is a transient response to early fasting. 
• Increased gluconeogenesis: The synthesis of glucose and its subsequent release into the circulation are vital hepatic functions during fasting. The carbon skeletons for gluconeogenesis are derived primarily from gluconeogenic amino acids and lactate from muscle, and glycerol from adipose. Gluconeogenesis, favored by activation of fructose 1,6-bisphosphatase (due to a drop in its inhibitor, fructose 2,6-bisphosphate) and by induction of phosphoenolpyruvate (PEP) carboxykinase by glucagon, begins four to six hours after the last meal and becomes fully active as stores of liver glycogen are depleted. Gluconeogenesis plays an essential role in maintaining blood glucose during both overnight and prolonged fasting.
• Whereas acetyl CoA cannot be used as a substrate for gluconeogenesis, the acetyl CoA produced by fatty acid oxidation is an allosteric activator of pyruvate carboxylase (and an allosteric inhibitor of pyruvate dehydrogenase), and thus pushes pyruvate to gluconeogenesis

glucose 6-phosphatase

gluconeogenic amino acids and lactate from muscle, and glycerol from adipose

Whereas acetyl CoA cannot be used as a substrate for gluconeogenesis, the acetyl CoA produced by fatty acid oxidation is an allosteric activator of pyruvate carboxylase (and an allosteric inhibitor of pyruvate dehydrogenase), and thus pushes pyruvate to gluconeogenesis

• Increased fatty acid oxidation: The oxidation of fatty acids derived from adipose tissue is the major source of energy in hepatic tissue in the postabsorptive state. The fall in malonyl CoA due to phosphorylation (inactivation) of acetyl CoA carboxylase by activated protein kinase (AMPK) removes the brake on carnitine palmitoyl transferase-1 (CPT-1), allowing β-oxidation to occur.
• [Note: Fatty acid oxidation provides the NADH and the adenosine triphosphate (ATP) required by the liver for gluconeogenesis.]
• Increased synthesis of ketone bodies: The liver is unique in being able to synthesize and release ketone bodies (primarily 3-hydroxybutyrate,  for use as fuels by peripheral tissues. [Note: The liver cannot use ketone bodies as a fuel] Ketogenesis is favored when the concentration of acetyl CoA, produced from fatty acid metabolism, exceeds the oxidative capacity of the TCA cycle. Significant ketogenesis starts during the first days of fasting. [Note: Unlike fatty acids, ketone bodies are water-soluble, and appear in the blood and urine by the second day of a fast.] The availability of circulating ketone bodies is important in fasting because they can be used for fuel by most tissues, including brain tissue, once their level in the blood is sufficiently high. This reduces the need for gluconeogenesis from amino acid carbon skeletons, thus preserving essential protein. [Note: Ketogenesis releases CoA, ensuring its availability for continued fatty acid oxidation.]

The oxidation of fatty acids derived from adipose tissue

Fatty acid oxidation

The fall in malonyl CoA due to phosphorylation (inactivation) of acetyl CoA carboxylase by activated protein kinase (AMPK) removes the brake on carnitine palmitoyl transferase-1 (CPT-1)

True

concentration of acetyl CoA, produced from fatty acid metabolism, exceeds the oxidative capacity of the TCA cycle

• Increased degradation of TAG: The activation of hormone-sensitive lipase and subsequent hydrolysis of stored TAG are enhanced by the elevated catecholamines epinephrine and, particularly, norepinephrine. These compounds, which are released from the sympathetic nerve endings in adipose tissue, are physiologically important activators of hormone-sensitive lipase. [Note: Glucagon also activates the lipase.]
• Increased release of fatty acids: Fatty acids obtained from hydrolysis of stored TAG are released into the blood. Bound to albumin, they are transported to a variety of tissues for use as fuel. The glycerol produced following TAG degradation is used as a gluconeogenic precursor by the liver. [Note: Fatty acids are also converted to acetyl CoA, which can enter the TCA cycle, thus producing energy for the adipocyte.]
• Decreased uptake of fatty acids: In fasting, lipoprotein lipase activity of adipose tissue is low. Consequently, circulating TAG of lipoproteins is not available for TAG synthesis in adipose tissue

Resting muscle uses fatty acids as its major fuel source. By contrast, exercising muscle initially uses its glycogen stores as a source of energy. During intense exercise, glucose 6-phosphate derived from glycogen is converted to lactate by anaerobic glycolysis. As these glycogen reserves are depleted, free fatty acids provided by the mobilization of TAG from adipose tissue become the dominant energy source

Glucose transport into skeletal muscle cells via insulin-dependent glucose transport (GLUT-4) proteins in the plasma membrane and subsequent glucose metabolism are depressed because of low levels of circulating insulin

• During the first two weeks of fasting, muscle uses fatty acids from adipose tissue and ketone bodies from the liver as fuels.
• After about three weeks of fasting, muscle decreases its use of ketone bodies and oxidizes fatty acids almost exclusively.
• This leads to a further increase in the already elevated level of circulating ketone bodies. [Note: The increased use of ketone bodies by the brain as a result of their increased concentration in the blood is correlated with the decreased use of these compounds by the muscle.]

• During the first few days of fasting, there is a rapid breakdown of muscle protein, providing amino acids that are used by the liver for gluconeogenesis. [Note: Alanine and glutamine are quantitatively the most important gluconeogenic amino acids released from muscle. They are produced by the catabolism of branched-chain amino acids ]
• By several weeks of fasting, the rate of muscle proteolysis decreases because there is a decline in the need for glucose as a fuel for the brain, which has begun using ketone bodies as a source of energy

Alanine and glutamine

• During the first days of fasting, the brain continues to use glucose exclusively as a fuel.
• [Note: Blood glucose is maintained by hepatic gluconeogenesis from glucogenic precursors, such as amino acids from proteolysis and glycerol from lipolysis.]
• In prolonged fasting (greater than two to three weeks), plasma ketone bodies  reach significantly elevated levels, and replace glucose as the primary fuel for the brain.
• This reduces the need for protein catabolism for gluconeogenesis. The metabolic changes that occur during fasting ensure that all tissues have an adequate supply of fuel molecules.

• As fasting continues into early starvation and beyond, the kidneys play important roles.
• Kidney expresses the enzymes of gluconeogenesis, including glucose 6-phosphatase, and in late fasting about 50% of gluconeogenesis occurs here.
• Kidney also provides compensation for the acidosis that accompanies the increased production of ketone bodies (organic acids).
• The glutamine released from the muscle's metabolism of branched-chain amino acids is taken up by the kidney and acted upon by renal glutaminase and glutamate dehydrogenase, producing α-ketoglutarate that can enter the TCA cycle, plus ammonia.
• The ammonia picks up H+ from ketone body dissociation, and is excreted in the urine as NH4+, decreasing the acid load in the body. In long-term fasting, then, there is a switch from nitrogen disposal in the form of urea to disposal in the form of ammonia

• The ammonia picks up H+ from ketone body dissociation, and is excreted in the urine as NH4+, decreasing the acid load in the body.
• In long-term fasting, then, there is a switch from nitrogen disposal in the form of urea to disposal in the form of ammonia

• Abdominal fat cells are much larger and have a higher rate of fat turnover than lower body fat cells.
• The abdominal adipocytes are also hormonally more responsive than fat cells in the legs and buttocks.
• Because men tend to accumulate the readily mobilizable abdominal fat, they generally lose weight more readily than women do.
• Furthermore, substances released from abdominal fat are absorbed via the portal vein and, thus, have direct access to the liver. Fatty acids taken up by the liver may lead to insulin resistance  and increased synthesis of triacylglycerols, which are released as very-low-density lipoprotein (VLDL). By contrast, free fatty acids from gluteal fat enter the general circulation, and have no preferential action on hepatic metabolism

• four to five servings of fruit, four to five servings of vegetables, two to three servings of low-fat dairy per day, and <25 percent dietary intake from fat
• Reduces BP particularly if with low sodium

• The Mediterranean diet contains seasonally fresh food, with an abundance of plant material, low amounts of red meat, and olive oil as the principal source of fat
• high in fruits, vegetables, whole grains, beans, nuts, and seeds; include olive oil as an important source of monounsaturated fat; and allow low to moderate wine consumption. There are typically low to moderate amounts of fish, poultry, and dairy products, with little red meat
• Reduces LDL and some diseases (not HDL or TG)

• omega 6(<10% of total calories)--> reduce HDL and LDL
• omega 3 (<1%)--> reduce TG/no role on HDL or LDL
• Trans-->increase LDL/reduce HDL
• MUFA-->reduce LDL/HDL
• Saturated--> increase LDL/no effect on HDL

oxidation of polyunsaturated fatty acids

Dietary n-3 polyunsaturated fats suppress cardiac arrhythmias (highest effect), reduce serum triacylglycerols, decrease the tendency for thrombosis, lower blood pressure, and substantially reduce risk of cardiovascular mortality