BIOQUI - 04/07/2023

Understanding Cholesterol and Steroids

Structure and Origin of Cholesterol

• Cholesterol is derived from a cyclopentano-perhydrophenanthrene structure, consisting of four rings labeled A, B, C, and D. The D ring represents the cyclopentane.

• The classic cholesterol molecule contains 27 carbon atoms with a hydroxyl group at position 3. It serves as a precursor for steroid hormones, bile acids, and vitamin D.

Steroid Hormones Derived from Cholesterol

• Steroid hormones include sexual hormones (like progesterone and testosterone), adrenal hormones (such as aldosterone and cortisol), and other sterols like folic acid.

• Aldosterone and cortisol are two key adrenal hormones that share structural similarities with cholesterol but have slight modifications.

Functions of Bile Acids

• Bile acids, such as cholic acid formed in the liver, aid in fat absorption by being stored in the gallbladder before reaching the intestine.

Importance of Ergosterol

• Ergosterol is a steroid found in fungi but not humans; it is targeted by antifungal medications due to its role in fungal cell membranes.

Role of Cholesterol in Health

• Cholesterol is essential for life; however, dietary intake can influence cholesterol deposits leading to conditions like atherosclerosis.

Cholesterol Transport Mechanisms

Lipoproteins: HDL vs LDL

• Cholesterol is transported via lipoproteins—proteins enriched with fats. Key types include HDL (high-density lipoprotein) known as "good" cholesterol and LDL (low-density lipoprotein), often referred to as "bad" cholesterol.

Implications for Cardiovascular Health

• High levels of HDL reduce the risk of atherosclerosis by removing cholesterol from tissues to the liver. Conversely, elevated LDL levels contribute to plaque formation within blood vessels.

Optimal Levels of Lipoproteins

Recommended Ranges for Health

• Ideal levels suggest that LDL should remain below 150 mg/dL while HDL should be above 45 mg/dL for optimal health benefits.

Special Considerations for At-Risk Patients

• For patients with diabetes or metabolic syndrome, it’s recommended that LDL levels do not exceed 110 mg/dL to minimize cardiovascular risks.

Peroxidation of Lipids: Causes and Effects

Understanding Lipid Peroxidation

• Lipid peroxidation occurs due to free radicals which can oxidize not only lipids but also proteins and nucleic acids. This process leads to rancidity affecting tissue integrity.

Health Consequences

How Are Fats Digested and Absorbed?

Role of Antioxidants in Lipid Control

• Antioxidants such as Vitamin E, Vitamin C, beta-carotenes, and selenium are essential in the diet to prevent lipid oxidation.

• These antioxidants help maintain the integrity of lipids found in cell membranes by preventing their degradation.

Daily Fat Intake Recommendations

• The World Health Organization recommends a daily fat intake of 60 to 150 grams, which constitutes about 30% of total caloric intake.

• Bile produced by the liver contains bile salts that aid in fat digestion; these salts originate from bile acids that undergo conjugation with other compounds.

Bile Acids and Their Functions

• Bile acids derived from cholesterol play a crucial role in emulsifying fats for better absorption.

• The production of bile acids is constant and serves as a mechanism for cholesterol elimination from the body through the intestines.

Enzymatic Breakdown of Fats

• Gastric lipase breaks down triglycerides during fat digestion, while pancreatic lipase further digests them into monoglycerides and glycerol.

• Glycerol can be obtained from dietary sources or produced via glycolysis; it is vital for various metabolic functions.

Additional Enzymes Involved in Fat Digestion

• Colipase activates pancreatic lipase, enhancing its ability to digest fats effectively.

• Phospholipase A2 hydrolyzes phospholipids, while esterases act on cholesterol esters and vitamin A esters to release fatty acids.

Enterohepatic Circulation of Bile Salts

• Bile salts are recycled through enterohepatic circulation; many return to the intestine after aiding fat digestion.

• Medications that bind bile acids can disrupt this circulation, leading to reduced reabsorption and potential issues with lipid absorption.

Consequences of Impaired Bile Salt Reabsorption

• A deficiency in bile salts can lead to malabsorption of lipids, resulting in steatorrhea (fatty stools).

• Steatorrhea indicates either decreased bile salt availability or impaired lipid absorption due to digestive issues.

Synthesis of Bile Acids from Cholesterol

• The rate-limiting step in bile acid synthesis involves cholesterol 7α-hydroxylase, which requires Vitamin C and NADPH as reducing agents.

• This enzyme's activity is crucial for producing sufficient amounts of bile acids necessary for effective fat digestion.

Classification of Bile Acids

• Primary bile acids include cholic acid and deoxycholic acid; secondary bile acids consist of lithocholic acid and others.

Bile Acids and Lipid Metabolism

Overview of Bile Acids

• Bile acids are categorized into primary bile acids, such as glycocholic acid (conjugated with glycine) and taurocholic acid (conjugated with taurine).

• Secondary bile acids are formed in the intestine from primary bile acids, which then re-enter the hepatic circulation. This process is known as the formation of bile salts.

• The conjugation of bile acids typically involves sodium or potassium salts, including sodium glycocholate and potassium taurocholate.

Lipid Absorption Process

• In the intestine, lipids are broken down by intestinal enzymes into fatty acids, cholesterol, lysophospholipids, and monoacylglycerols.

• These components enter lymphatic circulation as chylomicrons—large lipoproteins composed mainly of triglycerides and free fatty acids along with apoprotein B48.

Metabolic Pathways for Fatty Acids

• Fatty acids undergo esterification to form triglycerides; they can also be converted into bioactive compounds like prostaglandins and leukotrienes.

• Acetyl-CoA derived from fatty acids plays a crucial role in lipogenesis (fat synthesis), while its breakdown is referred to as lipolysis.

Key Processes in Fatty Acid Metabolism

• The metabolism of fatty acids includes both anabolic processes (lipogenesis occurring primarily in adipose tissue and liver) and catabolic processes (beta-oxidation).

• Lipogenesis begins with acetyl-CoA conversion to malonyl-CoA, requiring ATP, bicarbonate for carbon sources, and biotin as a cofactor.

Synthesis Regulation and Implications

• The initial reaction in fatty acid synthesis involves converting acetyl-CoA to malonyl-CoA through the action of acetyl-CoA carboxylase.

Energy Production from Fatty Acids

Role of Carnitine in Fatty Acid Transport

• Fatty acids return to acetyl-CoA as an energy source; long-chain fatty acids (10-12 carbon atoms) require carnitine for mitochondrial transport, while short-chain fatty acids do not.

• Carnitine acts as an intramitochondrial transporter between mitochondrial membranes, facilitating the entry of activated fatty acids. The catabolism can involve alpha, beta, or even gamma oxidation depending on the carbon being released.

Beta-Oxidation Process

• Primarily occurring in liver, muscle, heart, and adrenal cortex mitochondria, beta-oxidation starts with active fatty acid and ends with acetyl-CoA production. Each cycle reduces the fatty acid chain length by two carbons.

• In each cycle of beta-oxidation facilitated by oxidase enzymes, two carbon molecules are removed to form one acetyl-CoA while producing a smaller remaining fatty acid that continues cycling until fully oxidized.

Implications of Odd and Even Chain Fatty Acids

• Even-chain fatty acids (e.g., 16 carbons) yield multiple acetyl-CoA units; odd-chain fatty acids produce propionyl-CoA as the final product due to their structure.

Coenzymes and Energy Production

• The oxidation process requires coenzymes derived from niacin (NAD+) and riboflavin (FAD), which contribute to ATP formation. Prolonged fasting can lead to elevated free fatty acids in circulation causing potential lipemia.

• During prolonged fasting or diabetes mellitus, increased mobilization of free fatty acids occurs despite high blood sugar levels that cannot enter vital organs. This promotes lipolysis for energy generation through acetyl-CoA production.

Phases of Fatty Acid Oxidation

• The first phase involves triglyceride hydrolysis via lipases; next is the activation of the fatty acid using coenzyme A derived from pantothenic acid.

• Transport primarily targets the liver for further processing; subsequent phases include beta-oxidation leading to detoxification processes where excess acetyl-CoA may convert into ketone bodies if produced in surplus.

Hormonal Regulation and Lipolysis

• Hormones like adrenaline and glucagon activate protein kinases that stimulate triacylglycerol breakdown into free fatty acids circulating in blood bound to albumin for transport.

• Free fatty acids must bind proteins such as Z-proteins for cellular membrane passage before entering mitochondria for beta oxidation.

Importance of Carnitine in Mitochondrial Function

• Carnitine is crucial for transporting long-chain fatty acids into mitochondria; it is synthesized from lysine and methionine in organs like liver and kidneys but can also convert back after releasing its bound acyl group inside mitochondria.

Understanding the Role of Carnitine in Fatty Acid Transport

Mechanism of Fatty Acid Transport into Mitochondria

• The process begins with the formation of acylcarnitine from fatty acids and carnitine, facilitated by carnitine acetyltransferase.

• Acylcarnitine is then transported across the mitochondrial membranes by carnitine palmitoyltransferase I and II, allowing fatty acids to enter mitochondria for oxidation.

• Once inside, acylcarnitine releases CoA and regenerates free carnitine while releasing active fatty acids for beta-oxidation.

Beta-Oxidation Process

• Beta-oxidation involves a series of enzymatic reactions that break down fatty acids into two-carbon units, producing acetyl-CoA.

• Six groups of enzymes known as oxidases are responsible for cleaving carbon atoms from the fatty acid chain during this process.

• Odd-chain fatty acids yield propionyl-CoA instead of acetyl-CoA at their final cleavage step, which enters the Krebs cycle differently.

Energy Yield from Fatty Acid Oxidation

• Each round of beta-oxidation generates ATP through NADH and FADH2 production; specifically, 3 ATP per NADH and 2 ATP per FADH2.

• The total ATP yield can vary based on the number of cycles completed during oxidation; calculations depend on whether even or odd-chain fatty acids are processed.

Enzymatic Steps in Beta-Oxidation

• Key enzymes include enoyl-CoA hydratase and hydroxyacyl-CoA dehydrogenase, which facilitate hydration and further oxidation steps respectively.

• Each cycle produces one molecule of acetyl-CoA while shortening the original fatty acid chain until it becomes a shorter acyl-CoA.

Implications of Excessive Fatty Acid Oxidation

• Excessive oxidation leads to ketone body formation in the liver when there is an abundance of acetyl-CoA; these bodies can cause ketoacidosis if levels become too high.

• Ketoacidosis is particularly concerning in type 1 diabetes patients due to inhibited gluconeogenesis leading to hypoglycemia complications.

Alternative Pathways for Fatty Acid Metabolism

• Long-chain fatty acids may undergo oxidation in peroxisomes before entering mitochondria; however, this pathway does not produce ATP but shortens chains to eight carbons.

Energy Yield from Fatty Acid Oxidation

ATP Generation from Palmitic Acid

• The energy yield from fatty acids, specifically palmitic acid, is discussed. It is noted that the oxidation of palmitic acid generates four ATPs per cycle, leading to a total of 28 ATPs after seven cycles.

• Each enzyme in the Krebs cycle contributes an additional ten ATPs, resulting in a total of 80 ATPs generated from these enzymes. When combined with the previously mentioned 28 ATPs, this results in a cumulative total of 108 ATPs.

• After accounting for the two ATPs consumed initially to activate the fatty acid, the net yield from one mole of oxidized palmitic acid is 106 ATPs. This highlights the efficiency of fatty acids as high-capacity fuels compared to glucose.

Comparison with Glucose Oxidation