Lipid

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LIPIDS & LIPID DISORDERS ^¹

Classification
Biochemical
Clinical
Pathology

Lipids
General

Also see
Carbohydrates

From: R Brian Sommerville

Lipids: General

Basic molecules: Fatty acids
- Fatty acid definitions
  - Short chain: 4 to 8 carbons (C4 - C8)
  - Medium chain: C8 – C12
  - Long chain: C12/C14 - C20: Examples
    - Palmitic: C16
    - Stearic: C18
    - Linoleic: C18
    - Oleic: C18; Abundant in PN myelin
  - Very long chain (VLC): > C22
Lipid in muscle
- Abundance: 0.2% of muscle fiber
- Location: Type 1 > Type 2 muscle fibers
Fatty acids: Metabolism
- Metabolic pathways
  - Mitochondria
    - β-oxidation
    - Most ATP production
    - FA type: < C20
  - Peroxisome
    - β-oxidation
    - FA type: > C20
  - Microsome: ω & ω-1 oxidation
  - Muscle
    - FA type: Saturated long-chain
- Steps
  - Entrance into cell cytoplasm: Through sarcoplasmic membrane
  - Lipid Droplet fatty acids
    - Storage or Breakdown
  - Mitochondria
    - Import: From external to internal membrane
    - Fatty Acid release in mitochondria matrix to β-oxidation
Lipids (Fatty acids) as energy source
- Energy production: General
  - Common tissues: Skeletal & Cardiac muscle
  - Lipids used especially during fasting & prolonged exercise
  - Acute lipid oversupply
    - Inhibits glucose oxidation
    - Mitochondria
      - Preferentially switch from Carbohydrate to Fatty Acid utilization
- Heart; Kidney: 1° (Fatty acids)
- Skeletal muscle
  - Uses circulating fatty acids during
    - Postprandial period
    - Fasting & Exercise
  - Requires: Carnitine
    - Carnitine sources: Liver synthesis (~ 25% of requirements); Diet (Meat)
    - Carnitine storage: 98% in skeletal muscle
    - Carnitine in neonates: Low levels
  - Steps in fatty acid metabolism
    - Uptake & Activation
      - Proteins
        
        FATP1 (SLC27A1) : Very long chain fatty acids
        FATP4 (SLC27A4)
        
        Plasma membrane fatty acid-binding protein (FABP, GOT2 )
        
        Fatty acid translocase (FAT , CD36 )
        
        Cytoplasmic fatty acid-binding protein (FABPs)
        
        Skeletal muscle FABP3
      - Transport across mitochondrial membrane
        
        Carnitine shuttle
        
        OCTN2
    - Lipid droplets: Fatty acid storage in cytoplasm
      - Droplets
        
        Organelles derived from endoplasmic reticulum
        
        Core: Neutral lipid
        Core surrounded by
        
        Phospholipid monolayer
        
        Derived from: Cytosolic leaflet of ER membrane
        
        Regulatory enzymes
        
        Locations: Cytoplasm & Nuclei
        Biogenesis ¹²⁸
        
        Starts with: Neutral lipid synthesis in ER membranes
        
        Neutral lipid path: Move to
        
        Hydrophobic regions
        
        Between leaflets of ER phospholipid bilayer
        
        High neutral lipid concentrations
        
        Nucleate neutral lipid lenses
        
        Lenses
        
        Grow: By adding neutral lipid
        
        Bud: As lipid droplets into cytoplasm
        
        Fatty acids: Stored as triglycerides in lipid droplets
        
        Can be hydrolyzed back to Fatty acids by lipases
        
        Lipases: Adipose triglyceride lipase (PNPLA2)
        Activated by lipolysis
        
        Comparative Gene Identification-58 (ABHD5)
        Hormone sensitive lipase (HSL; LIPE)
        Monoglyceride lipase (MGL)
      - Lipid Droplet-ER contacts ¹¹⁸
        
        Interface between monolayer & bilayer-bounded organelle
        
        via Lipidic bridges
        
        Involved in: Maintenance of lipid droplet function
        Disorders
      - Lipid Disorders
    - Mitochondrial entry
      - Carnitine Palmitoyl Transferase IA (CPT IA)
      - Mitochondrial Trifunctional Protein (MTP)
      - Carnitine-Acylcarnitine Translocase (CACT; SLC25A20)
      - Carnitine Palmitoyl Transferase II (CPT II)
    - Metabolism: In Mitochondria
      - Electron-Transfer Flavoprotein (ETFA & ETFB)
      - ETFDH
      - β-oxidation
        
        1 mol Palmitate (C16:0) produces: 129 ATP
        FA Substrates
        
        Mitochondrial
        Peroxisome
        
        Muscle
        
        Reactions
        
        Dehydrogenation
        
        Hydration
        
        Dehydrogenation
        
        Thiolytic cleavage
- Brain: Ketones may be used
Disease testing
- Plasma total and free carnitine levels
  - Frequently lowered in FAO disorders
  - Levels always decreased in carnitine transporter deficiency
- Urinary organic acid profile
  - Most often normal or non-specific in adult FAO diseases
  - MADD: Abnormal excretion of
    - 2-hydroxyglutaric acid
    - ± Acylglycine derivatives
- Acylcarnitine profile (Plasma or Blood)
  - Most sensitive analysis for FAO disorders
  - More sensitive
    - After prolonged fast (> 12 h in adults)
    - During acute decompensation

Fatty Acid Transport
Cytoplasm→Mitochondria

From MW King

Fatty acids: Activated in cytoplasm to Acyl CoA
Acyl CoA transport: Through mitochondrial membranes
- Via acyl carnitine intermediate
- CPT I enzyme in outer mitochondrial membrane
- CPT II enzyme in inner mitochondrial membrane
Fatty acid-CoA in mitochondria is substrate for β-oxidation

Fatty Acid Oxidation

Lipid droplets in Muscle fibers: Large

Lipid Droplet

Lipid disorders: Biochemical classification

Pathways
1° Carnitine deficiencies: Deficient transport of carnitine
2° Carnitine deficiencies: Carnitine loss
- Acyl-CoA dehydrogenase deficiencies
  - SCAD(ACADS)
  - MCAD (ACADM)
  - MCKAT
  - LCAD (ACADL)
  - VLCAD (ACADVL)
  - LCHADD
    - Trifunctional enzyme deficiencies: HADHA; HADHB
  - Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (SCHAD)
  - ACAD9
- Carnitine-acylcarnitine translocase deficiency (CACT; SLC25A20)
- Electron transfer flavoproterin (ETF) deficiency (Riboflavin-responsive): ETFA; ETFB
- 2,4-Dienoyl-CoA reductase deficiency
Neutral lipid storage
- Neutral lipid storage disease with myopathy (NLSDM): ATGL; PNPLA2
- Neutral lipid storage disease with ichthyosis (NLSDI)
- Riboflavin-responsive MAD deficiency (ETFDH; ETFQo)
Plasma membrane L-carnitine transport: OCTN2
Lipid droplet-related
- Familial Recurrent Rhabdomyolysis, Childhood: Lipin-1
- Neutral lipid storage disease with myopathy (NLSDM) (ATGL; PNPLA2)
- Triglyceride storage disease with impaired long-chain fatty acid oxidation (NCIE2) (CGI-58)
Other lipid metabolism disorders
- ECHS1
- Pantothenate metabolism
  - Neurodegeneration with brain iron accumulation I : Pantothenate kinase 2
- Refsum disease: Phytanoyl-CoA hydrolase
- X-linked ichthyosis : Steroid sulfatase
- Sjögren-Larssen syndrome: FALDH
- SLS-like: ELOVL4; 6q14
- Chondrodysplasia punctata 2, X-linked dominant : 3β-hydroxysteroid-δ³,δ⁷-isomerase
- Nonsyndromic X-linked mental retardation (MRX63) : Fatty acid CoA ligase, long-chain 4 (FACL4)
- Fabry disease
- Mitochondrial disorders
Acquired disorders
- Isotretinoin toxicity
- Bortezomib: Lipid storage
- HIV: Lipodystrophy
- Chronic alcoholism: ? Myopathy
Also see

Lipid Myopathies: Clinical classification

Fixed weakness
- OCTN2: Carnitine transporter
- Riboflavin-responsive MAD deficiency (ETFDH)
- SCAD
- LSMFLAD (FLAD1)
- MCAD
- Multiple acyl–CoA dehydrogenase deficiency (GA II) (MADD)
- Neutral lipid storage disease with ichthyosis (NLSDI)
- Neutral lipid storage disease with myopathy
Exercise intolerance, Cramps & Myoglobinuria
- CPT II deficiency
- VLCAD
- Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (HADH)
- Trifunctional enzyme deficiencies (MTP) A & B
- MCKAT
- Phosphatidic acid phosphatase (LIPIN 1)

Disorder	Gene (Common mutation)	Clinical, Other	Muscle Lipid	Acylcarnitine Increase & Other	Carnitine
Weakness, Fixed
Carnitine deficiency	SLC22A5 (OCTN2)	Cardiomyopathy	+++ Type 1	Normal	Very low
SCAD	ACADS (Arg171Trp Gly209Ser)	Ophthalmoplegia	-	Butyrylcarnitine (C4) Ethylmalonic aciduria
Multiple acyl-CoA dehydrogenase (MAD)	ETFA	CoQ10 deficiency	+ Type 1	All lengths	Low
Multiple acyl-CoA dehydrogenase (MAD)	ETFDH	GI: Vomiting	++ Type 1	All lengths	Low
LSMFLAD	FLAD1	Scoliosis	++	Increased	?
Neutral lipid storage + Ichthyosis (NLSDI)	ABHD5	Hepatomegaly	+++ Type 1 & 2	Normal Leukocyte lipid vacuoles	Normal
Neutral lipid storage + Myopathy (NLSDM)	PNPLA2	Cardiomyopathy	+++ Type 1 & 2	Normal Leukocyte lipid vacuoles	Normal
Rhabdomyolysis ± Exercise intolerance & Cramps
CPT II deficiency	CPT2 (Ser113Leu 413delAG)		±	Long chain	Normal
VLCAD	ACADVL	Cardiomyopathy	±	Long chain	Mildly low
Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD)	HADH	Hepatic Hypoclycemia		Hydroxybutyrylcarnitine	Normal
Mitochondrial trifunctional protein (MTP) A	HADHA	Polyneuropathy	±	Long-chain Dicarboxylic & 3-Hydroxyacylcarnitines	Low
Mitochondrial trifunctional protein (MTP) B	HADHB	Cardiomyopathy Hepatic	±	Long-chain Dicarboxylic & 3-Hydroxyacylcarnitines	Low
Medium chain 3-ketoacyl-CoA thiolase (MCKAT)		Hepatic Hypoglycemia		3-Hydroxybutyric acid C12-C16 dicarboxylic acids, unsaturated
Medium-chain acyl-CoA dehydrogenase (MCAD)	ACADM (Lys304Glu)	Hepatic	±	Medium chain Acylglycines	Low
Phosphatidic acid phosphatase	LIPIN1		±	Normal	Normal

Lipid Biochemistry

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References
1. Neuromuscular Disorders 2010;20:693–700, J Clin Med 2018;7(12)

6/16/2021

LIPIDS & LIPID DISORDERS 1