Fatty Acid Metabolism

Overview – Fatty Acid Metabolism

Structure
- long chain of carbons with carboxyl group on one end
- can have a variable amount of double bonds
  - double bonds make a fat unsaturated
  - naturally in a cis configuration
    - trans fats are unnatural and created via hydrogenation of vegetable oils
      - ↑ risk of atherosclerosis
  - double bonds ↓ melting temperature
    - plant fat (e.g. olive oil) is unsaturated and liquid at room temperature
    - animal fat (eg. butter) is saturated and solid at room temperature
- nomenclature
  - e.g. palmitic acid
    - C16:0
      - 16 carbons with no double bonds
        
        numbered with carboxyl carbon as 1
  - e.g. linoleic acid
    - C18:2 (9,12)
      - 18 carbons with 2 double bonds (one at the 9th and one at the 12th carbon)
  - omega system
    - count opposite to the numbered system (i.e. carboxyl carbon is counted last)
    - used to number unsaturated fats
    - e.g. linoleic acid
      - omega 6 family
      - double bond at position “12” is 6 in from the opposite side (18 carbons in total)
Essential fatty acids (FA)
- cannot be synthesized
- examples
  - linoleicacid
    - omega 6
    - can be used as a precursor for arachidonic acid
      - becomes an essential fatty acid if linoleic acid is absent
  - linolenic acid
    - omega 3
      - ↓ risk of CV disease
        
        remember: omega 3 saves you from triple bypass
      - found in cold water fish, nuts
Transport
see Lipoprotein topic

Synthesis

FA synthesis
- pyruvate (carbohydrate) → acetyl-CoA
  - activated by insulin
  - functions to store excess carbs as fat
  - occurs in the mitochondria via pyruvate dehydrogenase
- acetyl-CoA + oxaloacetate → citrate
  - shuttled out of mitochondria into cytoplasm
    - citrate shuttle
  - split back to acetyl-CoA and oxaloacetate
- acetyl-CoA + CO₂→ malonyl-CoA
  - catalyzed by acetyl-CoA carboxylase
  - biotin required
  - activated by insulin
- malonyl-CoA → CO₂ + 2 carbons on fatty chain
  - catalyzed by FA synthase
  - requires NADPH
  - humans make palmitic acid (16:0) as stored fat
    - only de novo fat possible
  - for 1 palmitic acid requires
    - 8 acetyl-CoA
    - 7 ATP
14 NADPH

Catabolism

Break down via β-oxidation
- occurs in hepatocytes, myocytes, adipocytes
  - neurons cannot use fat as energy
    - FAs do not cross BBB
- pathway location differs based on length of FAs
  - short/medium (2-12 carbons)
    - diffuse in mitochondria
  - long (14-20 carbons)
    - utilizes carnitine shuttle
      - carnitine added to FA in the intermembrane space of the mitochondria
        
        catalyzed by carnitine acyltransferase (CAT) -1
        
        inhibited by malonyl-CoA so as to prevent newly synthesized FAs from being degraded
      - carnitine: FA transported into the matrix
        
        catalyzed by the carnitine transporter
        
        primary carnitine deficiency
        
        caused by carnitine transporter defect
        
        presentation
        
        lethargy
        
        irritability
        
        nonketotic / hypoketotic hypoglycemia
        
        triggered by catabolic states (e.g., fasting or illness)
      - carnitine exchanged for CoA
        
        catalyzed by carnitine acyltransferase (CAT)-2
        
        clinical importance
        
        myopathic CAT deficiency
        
        presentation
        
        myoglobinuria
        
        muscle aches/weakness
        
        ↑ TG content in muscles
unable to use as energy
- provoked by prolonged use of muscle
- very long (>20 carbons)
  - oxidized in peroxisome
β-oxidation pathway
- occurs in the mitochondrial matrix
- reverses FA synthesis
  - removing an acetyl-CoA and producing NADH and FADH₂
    - catalyzed by fatty acyl-CoA dehydrogenase
      - two types
        
        long-chain acyl-CoA dehydrogenase (LCAD)
        
        medium-chain acyl-CoA dehydrogenase (MCAD)
      - blocked by ackee fruit toxin
  - creates most of the energy used by the liver
    - acetyl-CoA created in liver does not enter the citric acid cycle
      - forms ketones
        
        see Ketone bodies topic
- clinical importance
  - MCAD deficiency
    - presentation
      - non-ketotic hypoglycemia
      - C8-C10 acyl carnitines in the blood
        
        liver unable to break FAs down further than C8-C10
      - no ketone bodies
        
        liver unable to produce ketones from β-oxidation
      - fasting hypoglycemia
        
        liver unable to produce enough energy from β-oxidation to supply gluconeogenesis
      - symptoms often precipitated by infection or stress
    - treatment
low fat diet with frequent meals of high carbs

Introduction – Fatty Acid Metabolism

Fatty acid metabolism is the process by which the body breaks down fats and converts them into energy. Fatty acids are a major source of fuel for the body, particularly during times of fasting or low carbohydrate intake. They are also important building blocks for cellular membranes and play a role in the synthesis of hormones and other signaling molecules.

The process of fatty acid metabolism involves a series of biochemical reactions that occur in the cytoplasm and mitochondria of cells. The initial steps involve the breakdown of triglycerides, which are stored in adipose tissue, into fatty acids and glycerol. The fatty acids are then transported to tissues such as muscle and liver, where they can be further metabolized to generate energy.

Types of Fatty Acid Metabolism

There are two main types of fatty acid metabolism: beta-oxidation and fatty acid synthesis.

Beta-oxidation: Beta-oxidation is the process by which fatty acids are broken down into acetyl-CoA molecules, which can then enter the citric acid cycle to generate energy. This process occurs primarily in the mitochondria of cells and involves a series of enzymatic reactions that sequentially remove two-carbon units from the fatty acid chain.
Fatty acid synthesis: Fatty acid synthesis is the process by which fatty acids are synthesized from acetyl-CoA molecules. This process occurs primarily in the liver and adipose tissue, and is stimulated by insulin and other anabolic hormones. Fatty acid synthesis involves a series of enzymatic reactions that convert acetyl-CoA into fatty acids, which can then be stored as triglycerides in adipose tissue or used as a source of energy.

Both beta-oxidation and fatty acid synthesis are tightly regulated by a variety of hormones and signaling molecules, and defects in these pathways can lead to a range of metabolic disorders, including obesity, type 2 diabetes, and cardiovascular disease.

Studies – Fatty Acid Metabolism

There have been many studies investigating various aspects of fatty acid metabolism, including the regulation of beta-oxidation and fatty acid synthesis, the role of fatty acids in energy metabolism and signaling, and the implications of defects in these pathways for metabolic health. Here are a few examples of studies related to fatty acid metabolism:

Regulation of fatty acid oxidation: A study published in the journal Nature in 2011 identified a novel mechanism for regulating beta-oxidation of fatty acids. The study found that the enzyme SIRT3, which is activated by caloric restriction, promotes fatty acid oxidation by deacetylating and activating the enzyme LCAD. This discovery sheds light on the complex regulatory mechanisms that control fatty acid metabolism in response to changes in nutrient availability.
Role of fatty acids in insulin resistance: A study published in the Journal of Clinical Investigation in 2007 investigated the role of fatty acids in the development of insulin resistance, a hallmark of type 2 diabetes. The study found that high levels of fatty acids in the blood lead to the accumulation of toxic lipid metabolites in muscle and liver cells, which impair insulin signaling and promote insulin resistance. This research highlights the importance of maintaining healthy levels of fatty acids in the blood for metabolic health.
Fatty acid signaling in the brain: A study published in the journal Nature in 2014 investigated the role of fatty acid signaling in the brain. The study found that the fatty acid oleic acid acts as a signaling molecule in the brain, regulating appetite and energy metabolism. This discovery could have implications for the development of new treatments for obesity and other metabolic disorders.
Fatty acid metabolism in cancer: A study published in the journal Nature in 2016 investigated the role of fatty acid metabolism in cancer cells. The study found that cancer cells rely on fatty acid oxidation for energy production, and that targeting this pathway could be a promising strategy for cancer therapy. This research highlights the importance of understanding fatty acid metabolism in the context of disease.

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Overview – Fatty Acid Metabolism

Introduction – Fatty Acid Metabolism

Types of Fatty Acid Metabolism

Studies – Fatty Acid Metabolism

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