Metabolic Inter-relationships in Disease (Ethanol) Flashcards
Metabolism of Alcohol
Ethanol is oxidized to _____ and _____ in the body and yields about _____ kcal/g – which is more than carbs and proteins but less than fat. Chronic Alcohol consumption inhibits normal metabolic pathways
Each one of these “standard drinks” contains _____ grams of alcohol
CO2
H2O
7
14
Alcohol Consumption in US
_____ of individuals consume alcohol
5% consume >_____ drinks daily (10-15g alcohol/drink)
Maximum recommended daily intake Women 22-30g alcohol/day
Men 33-45g alcohol/day
Short term ingestion of 80g alcohol or 6 beers over several days leads to _____
Daily ingestion of 80+ g daily over 10-20 years generates significant risk for _____
50-70%
2
reversible disease
severe injury
Chronic Alcoholism leads to
Malnutrition
_____
Diminished _____
anemia
immune function
Alcohol ingestion and metabolism
cytosol

Small amphipathic molecule absorbed from intestines by _____.
0-5% enters gastric mucosal cells of _____ (metabolized)
Rest enters blood goes to _____ where 85-95% is metabolized.
Rest metabolized in _____ also in liver
in cytosol: ethanol converted to acetaldehyde by _____
in mitochondria: acetylaldehyde converted to acetate by _____
passive diffusion upper GI liver microsomal ethanol oxidizing system (MEOS) alcohol dehydrogenase acetaldehyde dehydrogenase
Alcohol ingestion and metabolism
alcohol is very readily absorbed versus carbs etc; no _____ step in intake/breakdown of alcohol > toxic complications
conversion from ethanol to acetaldehyde increase the _____ in cytosol
acetaldehyde can easily _____ the mitochondrial matrix, and the conversion into acetate also increasing the _____ in mitochondria
rate limiting
NADH pool
cross
NADH pool
Alcohol dehydrogenase and Acetaldehyde dehydrogenase
Alcohol dehydrogenase 1 (ADH1)-cytosolic
- present in high levels in the liver- accounts for 3% of all soluble protein
- _____ Km - high affinity
- utilizes _____
Acetaldehyde dehydrogenase 1- mitochondrial
- oxidizes acetaldehyde to acetate
- _____ Km - high affinity
- Utilizes _____
- accumulation of _____ causes nausea and vomiting
low NAD+ low NAD+ acetaldehyde
What are the likely fates of Acetyl CoA produced?
in mito: _____ NADH ratio, TCA will be _____; goes into _____ formation
in cytosolic: acetyl CoA formed from _____; goes into _____ synthesis > results in the fatty liver appearance
high
inhibited
ketone body
acetate
FA/cholesterol
Genetics and Ethanol Metabolism
Common Allelic variant of ALDH results in an inactive enzyme- Homozygous individuals are considered _____ Alcoholics treated with ALDH inhibitors to help them _____
CANCER- Chronic ethanol consumption is associated with an increased risk of _____ cancer. Elevated acetaldehyde may be the carcinogenic factor- generates toxic protein _____.
ADH4- gastric alcohol dehydrogenase
Found in upper GI tract, Gingiva and mouth
Has highest _____ activity of all isozymes, Km=58mM
Ethanol concentration high in upper GI, example Beer is approx.
0.8M ethanol, therefore generates a lot of acetaldehyde
“protected from alcoholism”
abstain
upper aerodigestive tract
adducts
ADH
Genetics and Ethanol Metabolism
in case of inactive ALDH; cannot convert acetaldehyde to acetate, so they _____ often
acetaldehyde similar to glucose in _____; formation of _____, _____ mutations and _____ problems
puke glycation toxic adducts missense chromosomal
Oral manifestations associated with chronic alcoholism and/or ALD
_____: inflammation of tongue
_____: inflammation of gingiva
_____: inflammation of corners of the mouth
all due to nutritional deficiencye and/or dysregulation of _____
impact on dental care:
_____:
-periodontal probing
-tooth extraction (anything with wound healing is _____)
glossitis
gingivitis
cheilitis
liver function
uncontrolled/excessive bleeding
compromised
Toxic Effects of Ethanol Metabolism
Chronic ethanol abuse manifests itself as
- _____- Fatty liver- large, soft, yellow, greasy liver; vesicular lipid droplet within hepatocytes; earliest stage of alcohol liver disease; may be seen after moderate alcohol consumption, _____ loss of function, _____
- _____- hepatocyte swelling, necrosis, inflammation; may lead to early fibrosis liver dysfunction; occurs after repeated bouts of _____ alcohol consumption, may _____ or _____
- _____- pale, shrunken, nodules; slowly developing ischemic necrosis leading to fibrosis; may occur with in _____ or more slowly over a longer period of time; _____ liver damage leading to loss of function
hepatic steatosis
little
reversible
alcoholic hepatitis heavy resolve progress alcoholic cirrhosis permanent
Toxic Effects of Ethanol Metabolism
Acute effects of ethanol arise from increased NADH/NAD+ ratio indicated with
- The high NADH/NAD+ levels inhibit _____, inhibit _____ and inhibits flux through _____.
- Each of these inhibited pathways results in the diversion of _____.
- Alcohol-induced _____
- _____ because pyruvate
converted to lactate. - Ethanol increase transcriptional activation of numerous
genes involved in _____- contributing to _____
gluconeogenesis beta-oxidation TCA acetyl-CoA ketoacidosis hypoglycemia lipogenesis hepatic steatosis
Warburg effect- Metabolic requirements for cell proliferation
Warburg and co-workers showed in the 1920s that, under aerobic conditions, tumor tissues metabolize approximately _____ more glucose to lactate in a given time than normal tissues.
Since Warburg’s original studies:
Tumor suppressors and oncogenes exert direct
effects on metabolism: p53 promotes the _____ and _____; MYC induces _____ and _____.
Mutations in metabolic enzymes, specifically isocitrate dehydrogenase 1 (IDH1) and IDH2 and other citric acid cycle enzymes, are causally linked to familial and spontaneous _____
PPP
oxidative phosphorylation
glycolysis
glutamine metabolism
cancers
Warburg effect
tumor tissues 10x more glucose to lactate than normal tissues;
p53 - PPP, upregulate availabiltiy of _____
MYC - glycolysis, uptake fo xs levels of _____; unlimited amounts of glucose
and a _____ of glycolysis
NADPH
glucose
dysregulation
Warburg effect - metabolic requirements for cell proliferation
proliferating tissue draws parallels with _____; glucose
is in unlimited supply, only 5% in ox metabolism; rest goes
lactate formation; this process is _____
ATP is necessary to build biomass _____;
tumors have no
access to _____; able to generate the ATP they need
in the absence of _____ (no regulatory mechanism affecting
glucose transport)
tumor much faster rapidly oxygen (avascular) oxygen
Substrate Utilization in Heart Failure
Heart Failure
Heart failure is a chronic, progressive condition in which the heart muscle is unable to pump enough blood through to meet the body’s needs for blood and oxygen.
Common risk factors, obesity, hypertension, diabetes, atherosclerotic plaque formation
Cardiomyocytes require highly _____ form of energy. One pathogenic mechanism contributing to pumping inefficiency is cardiac metabolic dysregulation.
reduced
Substrate Utilization in Heart Failure
Causes of heart failure
The cause of heart failure is a weakened or
thickened cardiac muscle.
For example, in _____, the heart must pump extra forcefully against the additional blood pressure. First it becomes enlarged and thickened. Over time, the heart weakens, _____ develops, and it becomes less efficient at pumping. It can become _____ and weak or thickened and stiff.
chronic high blood pressure (hypertension)
scarring (fibrosis)
larger (dilated)
Substrate Utilization in Heart Failure

Cardiomyocyte mainly uses _____ that enter into the cell and are converted in the mitochondria through the _____ (CPT-1 and CPT-2), and the _____ (CT) before being used by β-oxidation (β-Ox) to produce _____, _____, and _____.
Glucose enters into the cell and is transformed into pyruvate by _____.
Lactate enters into the cell and is transformed into pyruvate by_____.
FAs carnitine PT carnitiyl translocase FADH2 NADH acetyl CoA glycolysis lactate dehydrogenase
Substrate Utilization in Heart Failure (HF)
Early HF cardiomyocyte. FA utilization is _____, mitochondrial FA β-Ox decreases, uptake and metabolism of glucose _____.
End-stage HF cardiomyocyte. FA uptake and metabolism are significantly _____; although, the glucose uptake and metabolism is significantly _____. Thus _____ energy per until weight.
decreased
increase
depressed
enhanced
less
Substrate Utilization in Heart Failure (HF)
ESHF cardiomyocytes
no FA uptake at all; most of energy coming from _____ (has half the amount
of energy); the liver is _____, going to have synthesize adequate amount
of glucose; worsened if _____ individual, glucose uptake into cardiomyocytes
is regulated by _____; diabetics end up with ESHF
why FA is most ideal for cardiomyocetes, lots of _____ and takes stress
off the _____
glucose
stressed
diabetic
insulin
energy
liver
Take home messages
-Regulation of metabolism due to acute alcohol consumption is governed by high
_____
Initially alcohol consumption provides sufficient _____ for cell function
Chronic alcohol consumption leads to acetaldehyde induced mitochondrial damage and liver
dysfunction- contributing to alcohol induced hepatitis and ultimately _____.
Cancer cells preferentially synthesize _____ from pyruvate even in the _____ of O2. This process
yields more ATP than glucose oxidation in mitochondria over given _____- necessary for
biomass production
Cardiac myocytes (healthy) rely on _____ as source of energy. Over time heart
compensates for inability to adequately pump blood, becomes hypertrophic or scars and shifts metabolic substrates from fatty acids to _____ and/or _____.
NADH/NAD+
ATP
cirrhosis
lactate
presence
time period
fatty acid beta-oxidation
glucose
lactate
