Lipid Diseases

• Acylation stimulating protein (ASP)


  • Potent anabolic effects on human adipose tissue
• Adipose tissue - characteristics

  • Considered as an energetic store - TAG
  • Recently: active organ (adipose organ) with great role for maintenance of homeostasis and regulation of neuroendocrine and immune systems
  • Organ with multiple localization - visceral (more metabolically active) and subcutaneous (less active)
  • Wight (WAT) and brown (BAT) adipose tissue
  • Adipocytes of brown adipose tissue exist everywhere in subcutaneous and visceral adipose tissue, but the amount depends on the age, gender, temperature regiment, body weight, and dietary regiment
• Leptin


  • Regulates overall body weight by limiting food intake and increasing energy use
  • Prevents obesity - "antiobesity hormone"
  • Exerts effects on inflammatory processes
  • High concentrations can result in an abnormally strong immune response
  • Direct correlation between leptin levels and the development of atherosclerosis
• Adipokines

  • Synthesized by adipocytes
  • Leptin, adiponectin, resistin, adipsin, visfatin
  • Pro-inflammatory cytokines - TNF-α, IL-1, IL-6
  • IL-10b - pleiotropic effect
  • IL-8 - neutrophil chemotactic factor
  • Proteins involved in blood clotting, PAI-1, and angiogenesis (VEGF, NO)
• Diseases of lipid metabolism

  • Adipose tissue characteristics
  • Adipokines
  • Leptin
  • Leptin receptors (Ob-R)
• Leptin receptors (Ob-R)

  • 6 isoforms in 3 classes
  • Contain common extracellular domain, transmembrane, and variable intracellular domains
  • Long form Ob-Rb responsible for activating signal transduction pathways
  • Short forms responsible for bioavailability of leptin and mediate permeability via blood-brain barrier
  • Binding of leptin to receptors leads to dimerization, autophosphorylation, and activation of signaling pathways
• Agouti/melanocortin system


  • Regulates body weight homeostasis
• Obesity is associated with high-calorie diets, low physical activity, and various health risks such as cardiovascular diseases, stroke, and heart attacks
• Direct correlation between the amount of body fat and the circulating levels of leptin
• Adiponectin is an oligomeric glycoprotein involved in increasing insulin sensitivity and has various effects on energetic homeostasis, vascular activity, inflammatory processes, cell proliferation, and tissue remodeling
• In obese individuals, high level of leptin but no effect on appetite leads to "leptin resistance"
• Leptin receptors activation

  Binding of leptin to its receptors leads to their dimerization and autophosphorylation, attachment and activation of JAK-2, stimulation of several signaling pathways via STAT3, MEK/ERK, and PI3-K/Akt
• Leptin


  • Involved in the regulation of the neuroendocrine axis, inflammatory responses, blood pressure, and bone mass
• Deficiency of leptin leads to uncontrolled appetite, pathological obesity, insulin resistance, diabetes, and immune suppression
• Levels of leptin increase in the serum in obese individuals and drop during weight loss
• Mediate permeability of leptin via blood-brain barrier
• Fatty liver is characterized by the storage of a high amount of TAG in the liver, leading to various metabolic issues
• Leptin expression is under complex control, with higher levels in females compared to males
• Leptin resistance is the inability of the brain to sense signals for satiety
• Leptin receptors


  • Located in the hypothalamus and CNS, decrease appetite and food intake, neutralize the activity of neuropeptide Y, neutralize the natural ligand of the receptors of drugs that stimulate food intake, stimulate the synthesis of α-MSH, a suppressor of appetite
• Stages of liver damages

  Nonalcoholic steatohepatitis (NASH)
• Atherosclerosis - phases

  1. Endothelial dysfunction

  2. Formation of lipid deposits

  3. Advanced vessel lesion

  4. Nonstable fibrotic plaques
• Role of blood monocytes in Atherosclerosis

  1. Plasma LDLs undergo oxidation in the intima, attracting and activating blood monocytes

  2. oxLDLs are taken by activated monocytes via scavenger receptors, leading to transformation into lipid-laden "foam" cells

  3. oxLDLs are toxic for endothelial cells
• Mechanisms of NASH

  1. Initiated by risk factors including rich food and lack of exercise causing obesity and insulin resistance

  2. Obesity leads to hyperglycemia and hyperlipidemia, contributing to insulin resistance in adipose tissue and muscle

  3. Insulin resistance promotes lipolysis in adipose tissue and inhibits glucose uptake in muscle, leading to increased circulating FA and glucose

  4. Excessive FA and glucose infused into the liver undergo oxidation overload and are mainly used for TG synthesis

  5. ROS produced by overload of β-oxidation induces lipid peroxidation, inflammation, and fibrosis, developing steatosis to NASH
• Atherosclerosis


  Thickening and hardening of arterial walls, affecting primarily the intima of large and medium-sized muscular arteries, characterized by the presence of fibrofatty plaques or atheromas
• Steps in development of Atherosclerosis

  1. Chronic endothelial injury

  2. Accumulation of lipoproteins in intima (oxLDL)

  3. Monocyte adhesion to the endothelium and mobilization to the intima

  4. Activation of monocytes transforming to Foam cells

  5. SMC proliferation and ECM production

  6. Growth factors released

  7. Platelets adhesion
• Causes of Atherosclerosis
• Metabolism of ethanol in liver

  1. Exchange of ethanol - Alcohol DH, Aldehyde DH, CYP2E1 (MEOS), Catalase

  2. Inhibition of gluconeogenesis and stimulation of lipogenesis leading to fatty liver disease
• Fatty liver progression

  1. NAFLD - Non-alcoholic fatty liver disease

  2. NASH - Nonalcoholic steatohepatitis