metab final

what are the guidelines for alcohol consumption

• drink in moderation and limit intake to 2 drinks/day or less for men and 1 drink/day or less for women

how many calories does alcohol provide and what factor determines how much the total caloric content is

• ethanol consumed in alcoholic beverages providing 7kcal/g

  • empty calories; no metabolic benefit

  • can account for 10% of energy intake in moderate consumer and up to 50% in alcoholics

how is alcohol absorbed and metabolized (broadly)

• rapid absorption throughout the entire GI tract and transported in circulation unaltered

• oxidatively metabolized in tissues (primarily liver)

  • final product: acetate

    • converted to acetyl coa and oxidized via krebs/tca cycle or FA synthesis

how is ethanol (i.e. alcohol) metabolized in hepatocytes?

• the majority of ethanol is oxidized by ADH in the cytosol, reduced NADH, a byproduct of the reaction accumulates when excessive ethanol is consumed

• the microsomal ethanol oxidizing system (MEOS) accounts for up to 20% of ethanol oxidation; location in the ER, the CYP2E1 enzyme is a cytochrome P450 mixed-function oxidase; NADPH is concurrently oxidized in the reaction

• the catalase system in peroxisomes plays a minor role in ethanol oxidation; the reaction requires H2O2

• the initial product of ethanol oxidation is acetaldehyde - transported to mitochondria and further oxidized to acetate by ALDH2; reduced NADH accumulates in mitochondria when excessive ethanol is consumed

• the final product of ethanol oxidation: acetate, will be metabolized to acetyl coa and used for energy via the TCA cycle or FA synthesis

what are the different pathways for alcohol metabolism in hepatocytes

• alcohol dehydrogenase pathway (ADH)

• microsomal ethanol oxidizing system (MEOS)

• catalase system

what are the cellular locations for alcohol metabolism in hepatocytes

• ADH: cytosol

• MEOS: smooth ER

• catalase: peroxisomes

what are the starting and end products for alcohol metabolism in hepatocytes

• starting:

  • ethanol

  • NAD+ → NADH

  • NAD+ → NADPH+

  • H+ + O2 → 2H2O

  • H2O2 → H2O

• end

  • acetaldehyde

  • ALDH2

  • acetate

what are the different enzymes and co factors for alcohol metabolism in hepatocytes

• ADH

  • NAD+ → NADH

  • alcohol dehydrogenase

  • acetaldehyde

  • acetate

  • ALDH2

• MEOS

  • CYP2E1 enzyme

  • NADPH

  • NADP+

  • H2O

  • ALDH2

  • FAD

  • FMN

  • cytochrome P450

• catalase

  • catalase

  • H2O2

  • H2O

what is the relative contribution of each pathway to ethanol metabolism (i.e. which ones are most active, when do others become active)

• ADH = ~78%

• MEOS = ~20%

• catalase = ~2%

what happens when alcohol dehydrogenase becomes saturated

• can become saturated when blood concentrations reach 1/3 or ¼ of toxic levels (50-80 mg/dL)

  • ethanol then metabolized by other systems

  • depletes NAD+ and impairs reactions requiring NAD+ (e.g. krebs, gluconeogenesis, FA oxidation)

  • causes high NADH:NAD ratio

what intermediates are formed in ethanol metabolism that have toxic implications

• acetaldehyde

what are symptoms of ethanol toxicity

• CNS depression: confusion, stupor, coma

• Respiratory depression: slow/irregular breathing (can lead to death)

• Hypoglycemia: especially in fasting state (↓ gluconeogenesis)

• Hypothermia: impaired thermoregulation

• Vomiting: risk of aspiration

• Seizures: often secondary to hypoglycemia

• Metabolic acidosis: ↑ NADH → lactic acidosis

• Bradycardia & hypotension: severe cases

• Loss of gag reflex: aspiration risk

know what systems for ethanol metabolism impact metabolism of other nutrients, drugs/medicines, free radicals, etc

• ethanol competitively inhibits hepatic conversion of retinol → interference through induced metabolic tolerance

  • ADH is identical to enzyme responsible for conversion (retinol dehydrogenase)

  • ethanol activates retinol dehydrogenase

  • leads to vitamin A deficiency

what are the consequences of excessive alcohol intake? know the 4 major effects and how they impact health & metabolism

• fatty liver cirrhosis

• lactic acidemia

• metabolic tolerance caused by:

  • acetaldehyde toxicity

  • high NADH:NAD+ ratio

  • substrate competition

  • induced metabolic tolerance

what are the consequences of acetaldehyde toxicity

• contributes to cancer pathophyisology

  • DNA adducts (chemical/molecule binding to DNA) → mutagenic/carcinogenic potential

do the health benefits of alcohol consumption outweigh the risks? why or why not?

• no the benefits of alcohol do not outweigh the risks

• risks include:

  • cancers

  • impaired protein synthesis → ↓ albumin, clotting factors

  • ↓ absorption of B vitamins, esp. thiamine, folate, B6

• Wernicke–Korsakoff syndrome: thiamine deficiency with chronic alcohol use

  • Researchers estimate it is undiagnosed in ~ 80% of patients

  • Components:

    • Wernicke’s encephalopathy (acute): confusion, ataxia, eye movement abnormalities

    • Korsakoff’s psychosis (chronic): severe memory impairment, confabulation (creation of false memories)

    • Impact: Can lead to permanent brain damage or death if untreated

how could nutritional interventions help mitigate alcohol-induced liver injury

• antioxidant nutrients and phytochemicals (e.g. polyphenols) → reduce inflammation and oxidative stres

• omega-3 fatty acids → support membrane integrity and mitochondrial function

• B-vitamins → support metabolism and methylation and may reduce fibrosis risk

• prebiotics and probiotics → may help restore intestinal barrier function and hepatic inflammation

what is atherosclerosis and what are the mechanisms for development

how do vascular reactive oxygen species (ROS) and inflammation contribute to atherosclerosis and how are they related (broadly)

what is the lipid hypothesis

what role does dietary cholesterol play in atherosclerosis if at all and what are the underlying metabolism-related mechanisms

are there any populations that may respond differently to dietary cholesterol

what are the major public health recommendations for dietary cholesterol intake currently

what is lipoprotein (a)

what is lipoprotein (a) influenced by

how does lipoprotein (a) relate to atherosclerosis

what is apolipoprotein E

what is apolipoprotein E influenced by

how does apolipoprotein E relate to atherosclerosis and brain related outcomes

what other atherogenic lipids might play a role in atherosclerosis

what are saturated and unsaturated fatty acids

what are the current intake guidelines for saturated and unsaturated fatty acids

how do saturated and unsaturated fatty acids relate to cardiovascular disease

what are trans fatty acids

what are the current intake guidelines for trans fatty acids

how do trans fatty acids relate to cardiovascular disease

what other factors might contribute to or protect against cardiovascular disease (broadly)

what is insulin resistance

what causes insulin resistance

what are the consequences of insulin resistance

what is type 2 diabetes and how does it differ from type 1

what are the different tests used to diagnose type 2 diabetes

what are the limitations to the different tests for T2D

how can these tests be used to diagnose T2D based on their limitations

what is metabolic syndrome

how is metabolic syndrome diagnosed (broadly)

what are some causes of metabolic syndrome

what are some consequences of metabolic syndrome

how does adipose tissue differ among individuals

how can adipose tissue contribute to metabolic dysfunction

what are the consequences of skeletal muscle insulin resistance

what causes hepatic glucose overproduction and hyperglycemia in glucose metabolism dysregulation

what happens to pancreatic beta cells in advancing metabolic disease

how do pancreatic beta cells contribute to elevated blood glucose levels

what happens in adipose tissue dysfunction

what promotes hepatic steatosis

how are muscle protein turnover and hepatic amino acid handling impacted by metabolic dysregulation

what are adipokines

how are adipokines related to metabolism and inflammation, etc

what are the major types of adipokines

what are GLP-1 receptor agonists and what are they used for

how do GLP-1 agonists work

how do GLP-1 agonists impact metabolism

what is metabolism and what is the overall goal (broadly)

what 2 intermediates tie pathways together in metabolism

what determines pathway direction for energy homeostasis in the cell

what are the differences between catabolism and anabolism

when might catabolism/anabolism be activated (thinking about fasting vs fed state vs postabsorptive vs starvation states)

what is the purpose of regulation and regulatory enzymes

what is AMPK

how is AMPK related to metabolism

how is AMPK affected by aging

what dietary components can activate AMPK

what roles do different organs play in macronutrient metabolism

what are the differences b/w fed, post absorptive, fasting, and starvation states

what major hormones are involved in regulation of metabolism and how

what are the differences b/w exercise and physical activity

how can exercise and physical activity influence health

why does exercise lead to increases in ATP production

how does exercise create a deficiency in ATP

how is ATP produced in muscle fibers

what are the differences b/w muscle fiber types

what determines someone’s muscle fiber types and how can they be impacted by exercise

what effects does exercise have on hormones and AMPK

how does exercise, hormones, and AMPK impact metabolism

what are the energy sources for skeletal muscle during rest

what are the different energy systems that supply ATP to muscle during exercise

how long and in what proportion does each energy system contribute to ATP production

what macronutrients are being used in skeletal muscle during different levels of VO2 max

why does muscle fatigue occur

what can reduce muscle fatigue

what are the benefits of exercise training and physical activity