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Introduction

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High-Yield Terms

  • Cholesterol ester: product of fatty acid esterification of the 3-OH catalyzed by ACAT or LCAT

  • Reverse cholesterol transport: process by which cholesterol is transferred from nonhepatic cells to HDLs and then transported back to the liver via blood

  • LDL: low-density lipoprotein, derived from de novo VLDL synthesized in the liver, referred to as “bad cholesterol”

  • HDL: lipoprotein particle involved in reverse cholesterol transport, referred to as “good cholesterol”

  • SREBP2: sterol-regulated element-binding protein 2, controls the expression of genes involved in hepatic cholesterol biosynthesis

  • SCAP: SREBP cleavage-activating protein, cleaves the transcription factor domain from ER-embedded SREBP, allowing it to migrate to the nucleus

  • Insig: insulin-regulated gene, regulates the activity of SCAP

  • Isoprenoid: any compound containing the 5-carbon organic molecule isoprene (also called terpene) with the formula: CH2=C−(CH3)−CH=CH2

  • Prenylation: process of attaching isoprenoid intermediates of the cholesterol biosynthetic pathway (farnesyl pyrophosphate and geranylgeranyl pyrophosphate) to proteins

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Cholesterol: Physiologically and Clinically Significant Lipid

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Cholesterol is a waxy lipophilic compound of the sterol family, which contains 3 six-membered rings, a five-membered ring, and a hydroxyalcohol (Figure 26-1). That cholesterol is a critical component of normal physiological function can easily be demonstrated when its biosynthesis is disrupted or when it accumulates in excess of normal physiological requirements (see Clinical Box 26-1 and 26-2). Loss of the activity of the terminal enzyme in de novo cholesterol biosynthesis (7-dehydrocholesterol reductase [DHCR7]) results in varying degrees of developmental malformation as well as behavioral and learning disabilities encompassing the disorder known as Smith-Lemli-Opitz syndrome (see Clinical Box 26-3). At the opposite end of the spectrum, excess cholesterol, in the vasculature, is a significant contributing factor in the development of coronary artery disease, vascular dysfunction, and atherosclerosis. It is this latter consequence of abnormal cholesterol that has led to the near-universal use of cholesterol biosynthesis–inhibiting drugs in the treatment of hypercholesterolemia.

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CLINICAL BOX 26-1: CHOLESTEROL VALUES

Standard fasting blood tests for cholesterol will include values for total cholesterol, HDL cholesterol (so-called “good” cholesterol), and LDL cholesterol (so-called “bad” cholesterol). Family history and lifestyle, including factors such as blood pressure and whether or not one smokes, affect what would be considered ideal versus nonideal values for fasting blood lipid profiles.

Total Serum Cholesterol
  • <200 mg/dL = desired values

  • 200–239 mg/dL = borderline to high risk

  • 240 mg/dL and above = high risk

HDL Cholesterol
  • With HDL cholesterol the higher the better

  • <40 mg/dL for men and <50 mg/dL for women = higher risk

  • 40-50 mg/dL for men and 50-60 mg/dL for women = normal values

  • >60 mg/dL is associated with some level of protection against heart disease

LDL Cholesterol
  • With LDL cholesterol the lower the better

  • <100 mg/dL = optimal values

  • 100 mg/dL-129 mg/dL = optimal to near optimal

  • 130 mg/dL-159 mg/dL = borderline high risk

  • 160 mg/dL-189 mg/dL = high risk

  • 190 mg/dL and higher = very high risk

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CLINICAL ...

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