🧬Biochemistry Unit 17 – Lipid Metabolism

Introduction to Lipids

• Lipids are a diverse group of hydrophobic or amphipathic molecules that play crucial roles in various biological processes
• Serve as structural components of cell membranes (phospholipids, cholesterol) and provide insulation and protection
• Function as energy storage molecules, primarily in the form of triacylglycerols (triglycerides) in adipose tissue
• Act as signaling molecules and hormone precursors (steroid hormones, eicosanoids)
• Facilitate the absorption and transport of fat-soluble vitamins (vitamins A, D, E, and K)
• Contribute to the flavor, texture, and satiety of foods
• Lipids are essential for maintaining cellular integrity, energy homeostasis, and various physiological functions

Lipid Structure and Classification

• Lipids are classified based on their chemical structure and properties into several main categories
  • Simple lipids: Fatty acids, triacylglycerols (triglycerides), and waxes
  • Complex lipids: Phospholipids, glycolipids, and lipoproteins
  • Sterol lipids: Cholesterol and its derivatives
  • Derived lipids: Eicosanoids, fat-soluble vitamins, and hydrocarbons
• Fatty acids are the building blocks of many lipids and consist of a carboxylic acid head and a hydrocarbon tail
  • Saturated fatty acids have single bonds between carbon atoms (palmitic acid, stearic acid)
  • Unsaturated fatty acids have one or more double bonds (oleic acid, linoleic acid)
• Triacylglycerols are composed of three fatty acids esterified to a glycerol backbone and serve as the primary form of energy storage
• Phospholipids have a hydrophilic head and two hydrophobic tails, forming the basis of cell membranes (phosphatidylcholine, phosphatidylserine)
• Cholesterol is a sterol lipid that modulates membrane fluidity and serves as a precursor for steroid hormones and bile acids

Lipid Digestion and Absorption

• Lipid digestion begins in the mouth with lingual lipase and continues in the stomach with gastric lipase, which hydrolyze a small portion of dietary triglycerides
• The majority of lipid digestion occurs in the small intestine, facilitated by pancreatic lipase, colipase, and bile salts
  • Bile salts emulsify large lipid droplets into smaller micelles, increasing the surface area for enzymatic action
  • Pancreatic lipase hydrolyzes triglycerides into free fatty acids and 2-monoacylglycerols
• Lipid absorption takes place in the small intestine, primarily in the jejunum
  • Free fatty acids, monoacylglycerols, and other lipid components are absorbed by enterocytes via passive diffusion and protein-mediated transport
  • Within enterocytes, triglycerides are resynthesized and packaged into chylomicrons along with cholesterol, phospholipids, and apolipoproteins
• Chylomicrons are secreted into the lymphatic system and eventually enter the bloodstream via the thoracic duct
• Short-chain and medium-chain fatty acids are directly absorbed into the portal vein and transported to the liver for oxidation

Lipid Transport in the Body

• Lipids are transported in the bloodstream as lipoproteins, which are spherical particles composed of a lipid core surrounded by a phospholipid and apolipoprotein shell
• The main classes of lipoproteins are chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL)
  • Chylomicrons transport dietary lipids from the intestine to peripheral tissues and the liver
  • VLDL is synthesized in the liver and transports endogenous triglycerides to peripheral tissues
  • LDL is derived from VLDL and delivers cholesterol to peripheral tissues and the liver via the LDL receptor
  • HDL removes excess cholesterol from peripheral tissues and returns it to the liver for excretion (reverse cholesterol transport)
• Apolipoproteins (ApoA, ApoB, ApoC, ApoE) on the surface of lipoproteins serve as ligands for receptors and cofactors for enzymes involved in lipoprotein metabolism
• Lipoprotein lipase (LPL) is an enzyme located on the surface of endothelial cells that hydrolyzes triglycerides in chylomicrons and VLDL, releasing free fatty acids for uptake by adjacent tissues
• Disorders of lipoprotein metabolism can lead to hyperlipidemia, atherosclerosis, and increased risk of cardiovascular disease

Fatty Acid Oxidation

• Fatty acid oxidation (beta-oxidation) is the primary pathway for the catabolism of fatty acids to generate energy (ATP) in mitochondria
• Before entering the mitochondria, long-chain fatty acids are activated by acyl-CoA synthetase in the cytosol, forming fatty acyl-CoA
• Carnitine palmitoyltransferase I (CPT-I) catalyzes the transfer of the fatty acyl group from CoA to carnitine, allowing the fatty acylcarnitine to cross the outer mitochondrial membrane
• In the mitochondrial matrix, the fatty acyl group is transferred back to CoA by carnitine palmitoyltransferase II (CPT-II)
• The beta-oxidation cycle involves four main steps: dehydrogenation, hydration, another dehydrogenation, and thiolysis
  • Each cycle shortens the fatty acyl-CoA by two carbon atoms and releases one acetyl-CoA, NADH, and FADH2
  • Acetyl-CoA enters the citric acid cycle for further oxidation
  • NADH and FADH2 are used in the electron transport chain to generate ATP
• The complete oxidation of a fatty acid yields a large amount of ATP compared to carbohydrates (palmitic acid: 106 ATP)
• Ketone bodies (acetoacetate, beta-hydroxybutyrate) are produced from acetyl-CoA when fatty acid oxidation rates exceed the capacity of the citric acid cycle, particularly during fasting or low-carbohydrate diets

Lipid Biosynthesis

• Lipid biosynthesis (lipogenesis) is the process of synthesizing complex lipids from simple precursors, primarily in the liver and adipose tissue
• Fatty acid synthesis occurs in the cytosol and involves the sequential addition of two-carbon units (malonyl-CoA) to a growing fatty acid chain
  • Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA from acetyl-CoA and bicarbonate
  • Fatty acid synthase (FAS) is a multi-enzyme complex that catalyzes the synthesis of palmitic acid (16:0) from acetyl-CoA, malonyl-CoA, and NADPH
• Triacylglycerol (triglyceride) synthesis occurs in the smooth endoplasmic reticulum and involves the sequential addition of fatty acyl-CoA to a glycerol-3-phosphate backbone
  • Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first and rate-limiting step, forming lysophosphatidic acid
  • Phosphatidic acid phosphatase (PAP) removes the phosphate group, yielding diacylglycerol (DAG)
  • Diacylglycerol acyltransferase (DGAT) catalyzes the final step, adding a third fatty acyl-CoA to form triacylglycerol
• Cholesterol synthesis occurs in the smooth endoplasmic reticulum and involves a complex series of reactions starting from acetyl-CoA
  • The rate-limiting step is the conversion of HMG-CoA to mevalonate by HMG-CoA reductase, which is the target of statins
  • The final steps involve the cyclization of squalene and subsequent modifications to form cholesterol
• Phospholipid synthesis shares some common steps with triacylglycerol synthesis but diverges to incorporate a polar head group (choline, ethanolamine, serine, or inositol) and two fatty acyl chains

Regulation of Lipid Metabolism

• Lipid metabolism is tightly regulated by hormones, transcription factors, and nutrient availability to maintain energy homeostasis
• Insulin is the primary anabolic hormone that promotes lipid synthesis and storage
  • Stimulates glucose uptake and lipogenesis in adipose tissue and the liver
  • Activates lipoprotein lipase (LPL) to increase fatty acid uptake and triglyceride storage in adipose tissue
  • Inhibits hormone-sensitive lipase (HSL) to reduce lipolysis and fatty acid release from adipose tissue
• Glucagon and catecholamines (epinephrine, norepinephrine) are catabolic hormones that promote lipid breakdown and mobilization during fasting or stress
  • Activate hormone-sensitive lipase (HSL) to increase lipolysis and fatty acid release from adipose tissue
  • Stimulate fatty acid oxidation in the liver and muscle
• Transcription factors, such as sterol regulatory element-binding proteins (SREBPs) and peroxisome proliferator-activated receptors (PPARs), regulate the expression of genes involved in lipid metabolism
  • SREBP-1c promotes fatty acid and triglyceride synthesis in response to insulin and high-carbohydrate diets
  • SREBP-2 regulates cholesterol synthesis and uptake
  • PPARα promotes fatty acid oxidation and ketogenesis in the liver during fasting
  • PPARγ stimulates adipogenesis and lipid storage in adipose tissue
• AMP-activated protein kinase (AMPK) is a cellular energy sensor that is activated by low energy states (high AMP:ATP ratio) and promotes catabolic pathways, including fatty acid oxidation
• Nutrient availability, particularly the balance between carbohydrates and fats, influences the substrate preference for energy production and the regulation of lipid metabolism

Lipid Metabolism Disorders

• Disorders of lipid metabolism can lead to dyslipidemia, characterized by abnormal levels of lipids and lipoproteins in the blood
• Hypercholesterolemia is an elevation of total cholesterol and LDL-cholesterol levels, which increases the risk of atherosclerosis and cardiovascular disease
  • Familial hypercholesterolemia is a genetic disorder caused by mutations in the LDL receptor gene, resulting in impaired LDL clearance
  • Secondary causes include obesity, diabetes, hypothyroidism, and certain medications (progestins, corticosteroids)
• Hypertriglyceridemia is an elevation of triglyceride levels, often associated with low HDL-cholesterol and increased risk of pancreatitis and cardiovascular disease
  • Primary causes include familial combined hyperlipidemia and familial hypertriglyceridemia
  • Secondary causes include obesity, diabetes, alcohol abuse, and certain medications (estrogens, beta-blockers)
• Fatty liver disease is characterized by the accumulation of triglycerides in the liver, leading to hepatic steatosis and potential progression to inflammation (steatohepatitis), fibrosis, and cirrhosis
  • Non-alcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and metabolic syndrome
  • Alcoholic fatty liver disease is caused by excessive alcohol consumption
• Lipodystrophies are a group of disorders characterized by the selective loss or absence of adipose tissue, leading to ectopic lipid accumulation in the liver and muscle, insulin resistance, and metabolic complications
  • Congenital generalized lipodystrophy is a rare genetic disorder caused by mutations in genes involved in adipocyte differentiation and lipid storage (AGPAT2, BSCL2)
  • Acquired lipodystrophies can be associated with autoimmune disorders, HIV infection, and certain medications (protease inhibitors)
• Treatment of lipid metabolism disorders involves lifestyle modifications (diet, exercise), pharmacological interventions (statins, fibrates, niacin), and management of underlying conditions