Lecture 9: LIPID/CHO integration inflamation and brown fat stuff

Liporpotein lipase

• uptake of FA from blood into tissues is responsible for the formation of glycerol

• regulated by insulin

  • can also be made from extra carbs

Hormone sensitive lipase

• release of FAs from adipose tissues into the blood when you need more energy

• buring of fats 

• release triglycerides from the adipose tissues 

Cellular glucose and TCA cycle and fatty acids

• glucose is required for energy to be obtained from all other nutrients 

• fatty acids can be used to create acetyl-Co

• this can then enter into the krebs cycle and combine with oxaloacetate to create citrate 

• when there is low blood glucose, the liver takes over in making oxaloacetate using fatty acids to create acytl-CoA

  • this is required to make glucose

  • in gluconeogenesis

Ketogenesis in the absense of glucose 

• low CHO/low energy diets 

• situations of accelerated FA oxidation 

• prolonged fasting or exercise 

• uncontrolled T1D 

  • if you cannot get insulin then you cannot bring glucose from the blood into the body 

Ketogenesis - producs

• ketones

  • used for energy

  • excreted in urine

  • accumulate in blood

• this is the overflow pathway from acetyl coA

  • if there is carb available it will instead go through tca

Role of ketogenesis

• overflow pathway for acetyl CoA 

• spares glucose for RBC and brain that require it 

• catabolic pathwaty for FAs 

What are the 3 ketone bodies created in ketogenesis

• Acetoacetate

• Acetone

• B-hydroxybutryrate

  • this is most abundant

What controls the formation of ketone bodies

• glucagon 

  • activates 

• insulin 

  • inhibits 

• Key enzyme 

  • HMG CoA Synthase 

Ketone body synthesis pathway

• Fatty acids→ acetyl CoA → ketone bodies

  • enter blood circulation

  • go to all tissues or exhaled in breath

• Brain: Ketone bodies are converted into Acetyl CoA for usre in TCA to produce enerty

Liver ketones

• not used for energy

  • uses FAs and does gluconeogenesis

Ketone path from liver mitochondria onwards

• in liver mitochondria 

  • Acetyl CoA becomes acetoacetate whcih then can become B-hydroxybutryate (Reversible)

    • This uses NADH but B-hydroxybutryate produces an NADH

• Enters blood

  • Acetoacetate becomes acetone to be breathed out through diffusion into airway 

• After blood → in mitochondria of periphery 

  • Acetoacetate becomes acetyl-CoA 

  • B-Hydroxybutryate becomes acetoacetate and then becomes acetyl CoA as well

• Most tissues can use these ketones for energy 

  • skeletal muscles, brain etc

Ketone oxidation in peripheral tissues

• AcAc and BHB both become acetyl CoA and then can go through the TCA cycle to become ATP

glucose/Fatty acid cycle - Post prandial 

• Increased blood glucose, increased insulin 

  • increased lipoprotein lipase (creating fat stores by taking in triglycerides) 

  • Decreased hormone sensitive lipase activity (wont break down fats for energy)

  • Muscle → More glut 4 so more glucose uptake and less FFA uptake 

  • Liver → increased glycogensynthesis

  • Adipose tissue → Increased glucose uptake 

    • more storage of glucose 

• Overall more fat taken in and less FFA uptake 

  • normalized blood glucose levels through glucose uptake 

• Low FFA in the blood

Glucose/fatty acid cycle in a fasted state 

• low blood glucose → low insulin 

  • Liver → Gluconeogenesis → produce glucose to produce energy 

  • Muscle → Lower glucose uptake, increased FFA uptake 

    • needs fuel but wants to spare glucose for the cells that require it 

    • Requires adipose tissue to release FFAs

  • Increased hormone sensitive lipase

    • allows for the breakdown of FFAs from adipose tissues

  • Will have high FFA in the blood

Fasting state

• Low blood glucose 

• low insulin 

• high plasma FFAs 

• Dominant muscle fule: fatty acids 

• Dominant liver fuel: FFAs (B oxidation) 

  • The use of FFA in the liver spares glucose for the cells that cannot use FFAs 

• Main liver output

  • Glucose via gluconeogenesis

  • Ketones

Beta Oxidation

• Makes acetyl CoA

Atherosclerotic CVD and inflamation

• chronic inflammatory disease + disordered lipid and lipoprotein metabolism can lead to 

  • Immune cell infiltration 

  • atherosclerotic plaques 

  • plaque ruptures 

  • acute events

Acute inflammation

• Cause

  • injury, irritants, pathogens, tissue damage

• Time course

  • rapid, short lived (hours to days)

• Chemical mediators

  • short lived immune cells - release cytokines (inflammatory comoounds)

• Symptoms

  • redness, heat, swelling, pain 

• Outcomes 

  • resolution (goes away), tissue repair

Chronic inflammation

• Persistant - prolonged

• Cause

  • long term exposure to irritant, poor diet/lifestyle

  • body may have failed to eliminate acute inflammation

• Time

  • slow onset, long lasting

• Chemical mediators 

  • long-lasting immune cells - release cytokines (inflammatory compouds)

• Symptoms

  • persistant pain, disease

• Outcomes

  • tissue damage (internal and external), can lead to disease 

stages of Atherosclerotic disease

• Normal

• Fatty streak formation 

  • Injury → LDL cholesterol enters the wall and is oxidized → macrophase scavengar → create foam cell → fatty streak formed 

• Plaque accumulation 

  • Enlarging plaque with a platelets on top 

• Fibrous plaque formation 

  • lipid core with a fibrous cap on top 

• Fibrous cap rupture 

  • cap bursts, releases the lipids and creation of a clot 

Inflamation and atherosclerotic

• artery damage → LDL → oxLDL attracts immune cells 

• Macrophages → foam cells → plaque 

  • secrete pro-inflammatory cytokines and growth factors 

• Chronic secretion of inflammatory molecules destabilizes the plaque 

• cap ruptures → blood clot → blocked artery → heart attack or stroke

Importance of balance in CVD

• Balance of the pro and anti inflammatory agents control the progression of the disease 

  • more N-3 eicoisanoids can supress clotting 

Promotors of athersclerosis and inflammation

• polutions/toxins

• smoking 

• diabetes 

• LDL, sdLDLD, low HDL 

• Persistant inflamation (chronic infections)

• Diet and lifestyle 

  • sugars, refined carbs 

  • saturated and trans fats 

  • highly processed foods c

  • chronic stress/sleep deprivation

Inhibitors of atherosclerosis and inflammation

• physical activity 

• high HDL and low LDL

• Diet/lifestyle 

  • fibre (lower cholesterol by binding bile acids), control glucose 

  • food rich in antioxidants (vitamins, minerals, polyphenols, flavonoids)

  • Fruits, nuts, seeds and veggies 

    • MUFA, PUFA, n-3 fats 

Study on dietary fats effect on mortality and CVD risk

• 2 long cohort studies 

  • Nurses health study (all women)

  • Health professionals (MEN)

• Assess diet at baseline and every 4 years 

• free of disease at baseline 

• collect records on mortaliry, disease etc 

  • looking at outcomes of the different diets 

Results of replacing % energy from total carb with the same energy from fats

• Trans fats increased mortality, saturated fats also increased but less 

• monounsaturated decreased mortality, pUFA was more decreased 

• MUFA + PUFA subs reduced the risk 

• Trans fats increased and SFA moderately increased 

Importance of replacement of nutrients on the risk of coronary heart disease

• trans fats did not have significant change, SFA did not have significant change MUFA did not have significant change (confidence intervals)

• PUFA had significant decrease in risk 

• Complex carbohydrate also had significant decrease 

Impacts of replacing 5% of energt from SFA isocalorically

• replacement with PUFA (n-3 in particular) is associated with lower mortality, CVD, neurodegenerative and respiratory diseases

Summary of results from studies

• it is important to think about specific dietary fats that are beign replaced

• SFAs and refined CHA have around the same risk of coronary artery disease and mortality

• MUFA and PUFA, and Complex carbs → when substituting SFA improve the risk

• Among PUFAs, n-3 may have the greatest impact on risk of mortality from multiple diseases

Metabolic effects of Saturated fatty acids

• In liver: Lower LDL receptors 

• Obeserved effect: Increased LDL cholesterol 

Metabolic effects of fatty acids on blood cholesterol: Trans fatty acids

• In Liver: INcreased cholesterol synthesis 

• Observed effect on lipoprotein

  • Increased LDL cholesterol

  • Decreased HDL cholesterol

Cis-poly unsat fatty acids: metabolic effects on blood cholesterol

• Liporpotein effect in blood

  • Decreased LDL cholesterol 

Omega-6 Fatty acids: effects on blood cholesterol and metabolic effects

• in liver:

  • Increased LDL receptors 

  • Increased bile acid synthesis 

• Lipoprotein blood effects

  • Decreased LDL cholesterol 

Omega-3 fatty acids effecty on blood cholesterol and metabolic effects

• In liver: 

  • Fatty acid oxidation 

  • decreased VLDL synthesis 

• IN adipose tissue

  • Increased VLDL uptake 

• Lipoprotein level effects 

  • Decreased VLDL 

MUFA (eg olive oil) effects on blood cholesterol and their metabolic effects

• IN blood 

  • Decreased LDL oxidation 

• LIpoprotein level effect 

  • Decreased LDL cholesterol