biochem 3: hepatic metabolism

in basal fasting state, _____ is the primary source of serum glucose, and _______ provide additional energy.

glycogen and fatty acids

______ becomes important as the fast progresses

gluconeogenesis

In the starved fasting state, _____ is provided by gluconeogenesis. _______ become a significant source of energy for the brain, and other tissues rely largely on ______

glucose, ketone bodies, and other tissues rely largely on fatty acids

Defects in energy metabolism are generally inherited in an _______ and most often present in ________.

autosomal recessive manner, infancy or early childhood.

If not successfully treated, most of these can result in _____ due to ____ or _____

permanent brain damage due to severe hypoglycemia or liver damage.

carbohydrate disorders include

galactosemia

essential fructosuria

heritable fructose intolerance

glycogen storage diseases

pyruvate kinase deficiency

lipid disorders

medium-chain acyl coA dehydrogenase deficiency

Defects in galactose metabolism are detected in the _______

first few days after birth

symptoms include

vomiting, refusal to eat, jaundice, and cataracts (if treatment is not begun soon enough).

Galactose accumulates in both forms of galactosemia, and is converted to ______ in most tissues. Result is ______ leading to cataracts and possible _______

galactitol, osmolar imbalance, cataracts and kidney damage

in classic glactosemia, ________ also accumulates, which is toxic to the _______

galactose 1-phosphate, liver

treatment of galactosemia - Dietary restriction of _____. patients are at higher risk for deficiencies in ____ and ____

lactose dairy products; At higher risk for deficiencies in Calcium and Vitamin D

what mechanism is shut down in classical galactosemia? _____ to ____ with _____

Galactose 1 phosphate to glucose 1 phosphate with galactose 1-phosphate uridylytransferase

what mechanism is shut down in non-classical galactosemia

galactose --> galactose 1 phosphate with galactokinase

Fructose metabolism occurs almost exclusively in the _____, and is not subject to regulation except at ______

liver and is not subject to regulation, except at pyruvate kinase

fructose catabolism produces high quantities of ______ and _____, which combine to form ______

glycerol phosphate and fatty acids, which combine to form TAG

fructose consumption is associated with

hypertriglyceridemia

TG can be exported in VLDL, or remain in the liver and cause

steatosis

rapid and unregulated _________ by fructokinase with low concentrations of ________ result in high quantities of_____

unregulated conversion of ATP to ADP by fructokinase, together with low concentrations of inorganic phosphate (Pi) result in production of high quantities of uric acid

hyperuricemia is associated with

gout, kidney stones, HTN, CVD, insulin resistance

Defects in fructose metabolism are generally not detected until after

a child begins to wean.

Hereditary fructose intolerance can cause ________, while essential fructosuria is ________

severe hypoglycemia, while essential fructosuria is asymptomatic.

what mechanism is shut down in essential fructosuria

fructose --> fructose 1 P using fructokinase

what mechanism is shut down in hereditary fructose intolerance?

fructose 1 P --> glyceraldehyde with aldolase B

essential fructosuria

fructokinase

hereditary fructose intolerance -

aldose b deficiency

fructose 1 phosphate is toxic to the _____. it ties up _____, thus inhibiting ______ and ______

liver; phosphate, thus inhibiting ATP synthesis, and it inhibits glycogen phosphorylase

glycogen is a ______ structure and that synthesis involves _____ and _______

highly branched structure, and that synthesis involves glycogen synthase and branching enzyme

glycogenolysis requires the activity of

glycogen phosphorylase and debranching enzyme

glucose-6-phosphatase is required for release of

glucose from hepatocytes

there are several glycogen storage diseases (GSD) that can cause severe _______ and can often be treated by _______

severe fasting hypoglycemia, can often be treated by dietary modification

type 0 will be a deficiency in

glycogen synthase

glycogen synthase causes

fasting hypoglycemia and fed state hyperglycemia

type 1a is a deficiency in

glucose 6 phosphatase

type 1a deficiency causes

fasting hypoglycemic, glycogen accumulation in liver, hyperlipidemia

type III is a def in

debranching enzyme

type III causes

fasting hypoglycemia, glycogen accumulation in liver, glycogen with short outer branches

type IV is a def in

branching enzyme

type IV will cause

fasting hypoglycemia, glycogen accumulation in liver, glycogen with long outer branches

type VI is a def in

glycogen phosphorylase

type VI will cause

gasting hypoglycemia, glycogen accumulation in liver

dietary modifications for glycogen storage disease (GSD)

Avoid fasting

Low carb diet

Uncooked cornstarch or intragastric feeding at night

Decrease amount of glycogen stored in liver

The most common inborn error in metabolism is a defect in ______, called _____

fatty acid catabolism; medium chain acyl-CoA dehydrogenase deficiency.

deficiency in MCAD causes

Decreased ability of hepatocytes to generate energy for gluconeogenesis from fatty acids

Decreased ability of hepatocytes to generate ketone bodies

Accumulation of medium chain fatty acids in the liver

Decreased ability of hepatocytes to generate energy for gluconeogenesis from fatty acids, leading to

fasting hypoglycemia

Decreased ability of hepatocytes to generate ketone bodies leading to

leading to fasting hypoketonemia

Accumulation of medium chain fatty acids in the liver -

- these appear to be toxic to the mitochondria and can cause liver damage.

dietary management to MCAD

High carb diet & frequent feeding

the liver is the prinicpal site of ______ in humans

AA synthesis

liver contains all pathways for _____ of all ____, can convert the ___ to either ____ or _____

catabolism if all amino acids, and can convert the carbon skeletons to either glucose or fatty acids/ketone bodies

liver contrains the urea cycle, which converts ______ generated in AA metabolism (in liver AND extrahepatic tissues) to ______

Contains the urea cycle, which converts toxic ammonium ions generated in amino acid metabolism (in the liver AND extrahepatic tissues) to urea for excretion in the urine.

liver processes _____ generated in the gut by enteric and bacteralial catabolism of _______

Processes ammonium ions generated in the gut (by enteric and bacterial catabolism of glutamine)

liver produces nitrogen containing compounds, such as

nucleotides and heme

liver synthesizes the majority of

serum proteins

Hyperammonemia is a symptom of

urea cycle defects and certain liver diseases.

Liver cirrhosis also increases

serum levels of various amino acids.

In newborns with hyperammonemia, a ______ should be considered.

urea cycle defect

________ is the result of increased ammonia due to _______

Hepatic encephalopathy is the result of increased ammonia (and possibly other neural toxins, including some amino acids) due to cirrhosis of the liver.

Portosystemic shunting in cirrhosis decreases ________ and _______. generally, _____ and ____ are elevated

hepatic uptake of amino acids (which may be elevated to begin with due to a hypercatabolic state) and enteric ammonium ions. Generally, aromatic amino acids and methionine are elevated.

defects in ____ and ____ catabolism are associated with a number of diseases

phe and tyr

Phe is hydroxylated to Tyr by _______. Deficiencies in the hydroxylase or its cofactor, ______, results in ______

phenylalanine hydroxylase; tetrahydrobiopterin, result in PKU.

Accumulated phe inhibits transport of _________ causing altered _______ and leading to problems in ________

other large hydrophobic amino acids into the brain; neurotransmitter synthesis leading to problems in psychomotor development.

PKU will also cause decreased synthesis of ______, which may also cause _______ in older patients

catecholamines, mood disorders in older patients

phenypyruvate, produced by _______, accumulates in the serum and urine and causes a _______

transamination of phe, causing musky odor

Tyr is the precursor of

melanin - albinism

treatment involves

Restriction of dietary phe, and sometimes supplementation with large hydrophobic amino acids.

Phe is an

essential amino acid

tyrosinemia I and II and alcaptonuria are more rare than

PKU

tyrosinemia I and II present in _____.

infancy

tyrosinemia type I is associated with ______, ______, and death within the first year of life

liver failure, cabbage-like body odor, and death within the first year of life.

tyrosinemia I mechanism -

homogentisate --> fumarate and acetoacetate via fumarylacetoaetate hydrolase

type II may cause _____ and _____ problems

eye and skin lesions and neuro problems

tyrosinemia II occurs from what mechanism?

tyrosine --> p-hydroxyphenylpyruvate via tyrosine aminotransferase

alcaptonuria results in accumulation of _______, which oxidizes in ______ causing it to turn ______

homogentisate, which oxidizes in urine, causing it to turn dark red.

mechanism of alcaptonuria -

homogentisate --> fumarate and acetoacetate via homogentisate oxidase

later in life, accumulation in _____ may cause ______

cartilage may cause arthritic joint pain

in maple syrup disease, a _______ is deficient

alpha-keto dehydrogenase

the _____ and their _____ products accumulate

The branched chain amino acids and their alpha-keto transamination products accumulate.

maple syrup disease affects the bodys ability to break down certain amino acids -

leucine, isoleucine, and valine —

inability to breakdown certain AA will lead to their

toxic buildup in the blood and brain.

accumulation of ____ leads to ______ and death within _____ if untreated.

alpha-keto acids leads to severe neurological problems (death within 1 year if untreated)

treatment requires restriction of

dietary branched chain amino acids

careful management of hypercatabolic states (avoid fasting)

what diet is treatment for maple syrup disease

Low protein diet with carefully managed levels of leucine, isoleucine, and valine.