Biochemistry Flashcards: Lipids, Cholesterol, Bile Acids, Ketone Bodies, Eicosanoids, LSDs, and Cellular Organelles

This set of flashcards covers core concepts on lipid metabolism (cholesterol, bile acids, ketone bodies, eicosanoids), lysosomal and peroxisomal disorders, fatty acid oxidation, lipid digestion/absorption, and key cellular organelles—designed to scaffold exam preparation.

What is the primary site of de novo cholesterol synthesis and roughly what proportion of total synthesis occurs there?

The liver is the main site (about 50% of total daily cholesterol synthesis); all tissues can synthesize cholesterol, but the liver contributes the majority.

What is the rate‑limiting step of cholesterol synthesis and where does it occur?

The reduction of HMG‑CoA to mevalonate by HMG‑CoA reductase; this occurs in the endoplasmic reticulum/cytosol region and is the key regulatory step.

Differentiate between cholesterol and cholesterol esters in terms of structure and transport.

Free cholesterol is the structural membrane component with a hydroxyl group; cholesterol esters (CE) are formed by esterifying a fatty acid at C3 via ACAT, are more hydrophobic, stored in cells, and transported in plasma within lipoproteins.

Which enzyme esterifies cholesterol to form cholesterol esters intracellularly?

Acyl‑CoA:cholesterol acyl transferase (ACAT).

What is the fate of cholesterol esters in bile and how are they solubilized?

CEs are solubilized by bile salts or phospholipids in bile for transport and digestion.

What is the starting molecule for cholesterol synthesis and how is acetyl‑CoA supplied to the cytosolic steps?

Acetyl‑CoA is the starting molecule; mitochondrial acetyl‑CoA is transported to the cytosol via the citrate shuttle, with NADPH supplied mainly by the HMP shunt and malic enzyme.

What provides the reducing power (NADPH) for cholesterol synthesis?

NADPH supplied by the Hexose Monophosphate (HMP) shunt (pentose phosphate pathway) and by malic enzyme.

Name the two major roles of cholesterol disposal and the key enzyme involved in converting cholesterol for excretion.

Cholesterol is disposed by conversion to bile acids (then conjugated and excreted) and by secretion of free cholesterol into bile; rate-limiting step for bile acid synthesis is 7α‑hydroxylase (in bile acid formation).

Where does ketogenesis occur, what are the main ketone bodies produced, and what enzyme initiates ketone body synthesis?

Ketogenesis occurs in liver mitochondria; major ketone bodies are acetoacetate, β‑hydroxybutyrate, and acetone; the rate‑limiting enzyme is HMG‑CoA synthase (primarily in liver mitochondria) that forms HMG‑CoA.

Which enzyme converts HMG‑CoA to acetoacetate in ketone body synthesis?

HMG‑CoA lyase cleaves HMG‑CoA to yield acetoacetate (and acetyl‑CoA).

Explain the fate of acetoacetate and β‑hydroxybutyrate during ketolysis in peripheral tissues.

Acetoacetate is activated by CoA from Succinyl‑CoA via thiophorase (succinyl‑CoA:acetoacetate‑CoA transferase) to form acetoacetyl‑CoA, which is converted to two acetyl‑CoA molecules that enter the TCA cycle. β‑Hydroxybutyrate is oxidized to acetoacetate during its utilization.

Why can the liver not use ketone bodies for its own energy production?

The liver lacks thiophorase (succinyl‑CoA:acetoacetate CoA transferase), so it cannot convert acetoacetate to acetyl‑CoA for oxidation; RBCs lack mitochondria and cannot use ketones either.

Estimate the energy yield from oxidizing one molecule of acetoacetate and one molecule of β‑hydroxybutyrate.

Acetoacetate yields about 23 ATP; β‑hydroxybutyrate yields about 26 ATP (including oxidation to acetoacetate and subsequent acetyl‑CoA entry).

What is the approximate energy value of ketone bodies per gram, and why is this advantageous?

Ketone bodies provide about 5 calories per gram; they offer a metabolic energy advantage during fasting/starvation.

Describe the hormonal regulation of ketogenesis and the role of FOXA2.

Insulin inhibits ketogenesis by suppressing lipolysis; glucagon stimulates ketogenesis by increasing lipolysis. FOXA2 promotes HMG‑CoA synthase expression; glucagon activates FOXA2 via acetylation to boost ketogenesis, while insulin promotes FOXA2 phosphorylation and inactivation, reducing ketogenesis.

Define ketoacidosis and name common precipitating conditions.

Ketoacidosis is a dangerous acidosis caused by excess ketone bodies (acetoacetate and β‑hydroxybutyrate) lowering blood pH; commonly precipitated by uncontrolled Type I diabetes mellitus, chronic alcoholism, or prolonged fasting/starvation.

What are the major categories of eicosanoids and their precursors?

Major categories: Prostanoids (PGs, TXs, PGIs), Leukotrienes (LTs), and Lipoxins; all derived primarily from arachidonic acid, a 20‑carbon polyunsaturated fatty acid.

Which enzyme pathway is responsible for prostanoid formation and where does it occur?

The Cyclooxygenase (COX) pathway forms prostanoids (PGs, TXA2, PGI2) and occurs in the endoplasmic reticulum (ER). COX‑1 is constitutive; COX‑2 is inducible.

How do NSAIDs and aspirin affect eicosanoid synthesis?

Aspirin irreversibly inhibits COX‑1 and modestly affects COX‑2; NSAIDs like indomethacin or ibuprofen reversibly inhibit COX‑1; coxibs selectively inhibit COX‑2; corticosteroids inhibit phospholipase A2, reducing arachidonic acid release.

Name two key sphingolipidoses and their enzyme defects and hallmark features.

Tay‑Sachs: HEX A deficiency; GM2 ganglioside accumulation; no hepatosplenomegaly with progressive neurodegeneration and cherry‑red macula. Niemann‑Pick: sphingomyelinase deficiency; sphingomyelin and cholesterol accumulation; hepatosplenomegaly and foam cells.

What is Gaucher disease, its enzyme defect, and a classic cellular hallmark?

Gaucher disease: deficiency of glucocerebrosidase (β‑glucosidase); accumulation of glucocerebroside in macrophages, termed Gaucher cells with a crumpled tissue‑paper appearance; presents with hepatosplenomegaly, bone symptoms.

Describe I‑cell disease and its basic defect.

I‑cell disease (inclusion‑cell disease) is due to deficiency of N‑acetylglucosaminyl‑1‑phosphotransferase, causing failure to tag lysosomal enzymes with mannose‑6‑phosphate; lysosomal enzymes are secreted rather than delivered to lysosomes, leading to accumulation of undigested substrates.

What are peroxisomes, and name three peroxisomal disorders discussed?

Peroxisomes perform VLCFA β‑oxidation, ROS detoxification, and plasmalogen biosynthesis. Disorders include Zellweger syndrome (peroxisome biogenesis defect), Refsum disease (α‑oxidation defect in phytanic acid), and Adrenoleukodystrophy (X‑linked; ABCD1 transport defect for VLCFAs).

Explain the major roles of peroxisomes in lipid and ROS metabolism.

Peroxisomes are involved in VLCFA β‑oxidation, detoxification of reactive oxygen species via catalase, and plasmalogen synthesis (important for myelin); they also metabolize branched-chain fatty acids and bile acids.

What is the process of lipid digestion and absorption in the intestine and the role of chylomicrons?

Dietary triglycerides are emulsified by bile salts; pancreatic lipase (with co‑lipase) digests TGs to 2‑monoacylglycerol and free fatty acids; 2‑MG, LCFA, lysophospholipids, cholesterol form mixed micelles, absorbed by enterocytes; in enterocytes, TGs are reassembled in the SER with ApoB‑48, packaged by MTP, and secreted as chylomicrons via the lymphatic system; LPL in capillaries digests TGs in chylomicrons to FFAs; chylomicron remnants are cleared by the liver via ApoE.

What is the regulatory role of malonyl‑CoA in fatty acid oxidation?

Malonyl‑CoA inhibits CPT‑I, blocking entry of long‑chain fatty acids into mitochondria for β‑oxidation; this coordinates fatty acid synthesis and oxidation.

Where does de novo fatty acid synthesis occur and what are the key enzymes and regulatory steps?

Mainly in the liver (and adipose tissue). Key enzymes: acetyl‑CoA carboxylase (ACC) converting acetyl‑CoA to malonyl‑CoA (regulation by citrate activates, long‑chain acyl‑CoA inhibits; phosphorylation inhibits; insulin activates). Fatty acid synthase (FAS) performs 7 steps to make palmitate (C16:0).