Cholesterol Metabolism and Regulation
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Questions and Answers

What type of proteins does the endosome–lysosome pathway primarily degrade?

  • Proteins from the nucleus
  • Intracellular organelles
  • Membrane-bound receptors only
  • Extracellular and cell-surface proteins (correct)

What role does HDL play in cholesterol transport?

  • HDL delivers dietary triglycerides to adipocytes.
  • HDL unloads triglycerides and remaining cholesterol directly into cells.
  • HDL transfers cholesterol from peripheral cells back to the liver. (correct)
  • HDL is involved in the degradation of misfolded proteins.

Which proteolytic pathway is specifically associated with degrading proteins from the cytoplasm, nucleus, and endoplasmic reticulum?

  • Autophagic pathway
  • Ubiquitin–proteasome pathway (correct)
  • Mitochondrial pathway
  • Endosome–lysosome pathway

How do chylomicrons function in cholesterol transport?

<p>They deliver dietary triglycerides to adipocytes. (C)</p> Signup and view all the answers

How does the proteasome carry out protein degradation?

<p>By a highly targeted mechanism using ubiquitin (C)</p> Signup and view all the answers

What initiates the ERAD pathway?

<p>Identification of misfolded or aberrant proteins by quality control receptors. (B)</p> Signup and view all the answers

What is a key feature of the mitochondrion's proteolytic system?

<p>It is similar to proteolytic systems in prokaryotes (C)</p> Signup and view all the answers

What happens to misfolded proteins during the ERAD process?

<p>They undergo retrotranslocation and ubiquitination for degradation. (A)</p> Signup and view all the answers

Which enzyme is responsible for transferring ubiquitin from E1 to E2 in the ubiquitin-proteasome system?

<p>Ubiquitin-activating enzyme E1 (C)</p> Signup and view all the answers

What is the primary function of LDL in cholesterol transport?

<p>LDL transfers cholesterol from the liver to peripheral cells. (B)</p> Signup and view all the answers

What does the proteasome primarily degrade?

<p>Individual cellular proteins (C)</p> Signup and view all the answers

What does feedback inhibition by cholesterol involve?

<p>Cholesterol regulating the synthesis of its own production. (A)</p> Signup and view all the answers

What is the characteristic composition of the 26S proteasome?

<p>A 20S barrel and two 19S lids (B)</p> Signup and view all the answers

Which of the following statements correctly describes the cooperation between the endosome–lysosome and ubiquitin–proteasome pathways?

<p>Recent evidence suggests they cooperate. (D)</p> Signup and view all the answers

What is the significance of Scavenger Receptor-B1 in cholesterol transport?

<p>It helps HDL acquire cholesterol from peripheral cells. (C)</p> Signup and view all the answers

What mechanism is paired with the transfer of misfolded proteins during ERAD?

<p>Ubiquitination by an E3 ubiquitin ligase. (D)</p> Signup and view all the answers

What is the primary function of autophagy in cells?

<p>To remove unnecessary or dysfunctional components (C)</p> Signup and view all the answers

Which type of autophagy involves the formation of an autophagosome?

<p>Macroautophagy (D)</p> Signup and view all the answers

What role does the protein hsc70 play in chaperone-mediated autophagy?

<p>It recognizes and binds to specific protein substrates (D)</p> Signup and view all the answers

What occurs after the outer membrane of an autophagosome fuses with a lysosome?

<p>The contents are lysed and degraded (D)</p> Signup and view all the answers

Which of the following is NOT a type of autophagy?

<p>Cellular autophagy (D)</p> Signup and view all the answers

Which factor has been linked to defects in autophagy?

<p>Neurodegeneration and cancer (C)</p> Signup and view all the answers

In which type of autophagy are lysosomal membranes directly invaginated?

<p>Microautophagy (A)</p> Signup and view all the answers

What has become increasingly clear about the role of autophagy in non-starved cells?

<p>It contributes to cellular homeostasis. (B)</p> Signup and view all the answers

What could lead to the accumulation of autophagic vacuoles in aging cells?

<p>Inability of lysosomes to fuse with autophagic vacuoles (D)</p> Signup and view all the answers

How does the insulin receptor affect macroautophagy in aging cells?

<p>It maintains negative signaling that represses autophagy. (C)</p> Signup and view all the answers

What effect does an age-dependent decline in macroautophagy have on cells?

<p>Leads to energetic compromise (B)</p> Signup and view all the answers

What was observed in mice that followed a Fasting Mimicking Diet (FMD)?

<p>Enhanced regeneration in multiple systems (D)</p> Signup and view all the answers

What role does glucagon play in the process of macroautophagy?

<p>It enhances macroautophagy but is less effective in old cells. (C)</p> Signup and view all the answers

Which consequence is most likely a result of inadequate turnover of organelles in aging cells?

<p>Increase in free radical levels (D)</p> Signup and view all the answers

What was a significant finding related to calorie restriction in mice?

<p>It improved learning and memory. (C)</p> Signup and view all the answers

What is a potential consequence of the failure of macroautophagy in older organisms?

<p>Compromised metabolic health (A)</p> Signup and view all the answers

What maintains the low lysosomal pH of 4-5?

<p>V-ATPase pumping H+ into the lumen (A)</p> Signup and view all the answers

What is the primary function of the acid hydrolases present in lysosomes?

<p>Hydrolyze macromolecules to generate building blocks (D)</p> Signup and view all the answers

Which transporter activates mTOR in response to luminal arginine?

<p>SLC38A9 (D)</p> Signup and view all the answers

What role does mTORC1 play in cellular processes?

<p>Regulates the balance between anabolism and catabolism (B)</p> Signup and view all the answers

What does the cellular export of cholesterol from lysosomes primarily involve?

<p>NPC1/NPC2 proteins and SCARB2 (A)</p> Signup and view all the answers

Why is solute efflux important in lysosomes?

<p>To prevent osmotic pressure and membrane tension (C)</p> Signup and view all the answers

What distinguishes proton-coupled amino acid transporters from typical amino acid transporters?

<p>They use H+ for transport instead of Na+ (B)</p> Signup and view all the answers

Which of the following is NOT a function of mTOR?

<p>Degrade lysosomal components directly (A)</p> Signup and view all the answers

What is the function of S6K1 in mRNA translation initiation?

<p>It phosphorylates and activates substrates promoting translation. (D)</p> Signup and view all the answers

Which component is a part of the mTOR Complex 1 (mTORC1)?

<p>PRAS40 (B)</p> Signup and view all the answers

How does mTORC1 regulate mRNA translation at the ribosome?

<p>By phosphorylating 4EBP to promote eIF4E release. (A)</p> Signup and view all the answers

Which factor is NOT involved in the regulation of mTORC1 activity?

<p>GTP from RagC (A)</p> Signup and view all the answers

What role does 4EBP play in translation regulation?

<p>It sequesters eIF4E to inhibit translation. (D)</p> Signup and view all the answers

Which amino acid has been noted as a significant regulator in mTORC1 signaling?

<p>Arginine (C)</p> Signup and view all the answers

What mechanism leads to the recruitment of mTORC1 to the lysosome?

<p>SLC38A9 activating RagA to GTP-bound state. (B)</p> Signup and view all the answers

What is a primary role of mTORC1 in ribosome biogenesis?

<p>Coordinating stimuli for ribosome production. (D)</p> Signup and view all the answers

Flashcards

Cholesterol Transport to Liver

Cholesterol from cells is picked up by HDL and taken back to the liver.

LDL Receptor Uptake

LDL cholesterol is taken by peripheral cells or liver by specific receptor.

Chylomicron Delivery

Fat from food is carried by chylomicrons to fat cells (adipocytes).

ERAD Pathway

A process that removes misfolded proteins from the endoplasmic reticulum (ER).

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Quality Control Receptors

Proteins in the ER that recognize and mark misfolded or unassembled proteins for ERAD.

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ER-Membrane-Associated Complex

A complex in the ER that facilitates the removal of misfolded proteins.

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Protein Degradation

Misfolded proteins are transported to cytosol, ubiquitinated, and ultimately degraded.

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Feedback Inhibition

The process of cells regulating cholesterol production based on levels of needed cholesterol already in the body.

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Endosome-lysosome pathway

Degrades extracellular and cell-surface proteins, like receptors and ligands, and intracellular organelles.

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Ubiquitin-Proteasome pathway

Degrades proteins in the cytoplasm, nucleus, and ER.

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Mitochondrial proteolytic system

Has its own protein-degrading system, similar to prokaryotes.

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Proteasome

A protein complex that degrades proteins targeted by the ubiquitin-proteasome system.

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Ubiquitin-Proteasome system (UPS)

A pathway for targeted protein degradation using ubiquitin and a proteasome.

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Autophagy

The process lysosomes use to degrade cytoplasmic components, protein aggregates, and surplus organelles.

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Target protein and ubiquitin ligase

Ubiquitin is attached and the target protein X is marked for destruction, by the ubiquitin ligase E3.

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26S proteasome

A complex proteolytic enzyme made of the 20S barrel and two 19S regulatory units.

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Macroautophagy

The main type of autophagy, where the cell engulfs worn-out materials into vesicles (autophagosomes) that deliver them to lysosomes for degradation.

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Autophagosome

A double-membrane vesicle that transports material destined for degradation to lysosomes.

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Lysosome

Cell organelle containing enzymes that break down cellular waste and foreign material.

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Microautophagy

Type of autophagy where cellular materials are directly engulfed by invaginations (foldings) of the lysosomal membrane.

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Chaperone-mediated autophagy

A selective type of autophagy that depends on a chaperone protein (like hsc70) to target specific proteins for lysosomal degradation.

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Ubiquitination

A process that attaches ubiquitin proteins to target proteins, marking them for degradation by the proteasome.

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Lysosomal pH

The internal pH of lysosomes, typically around 4-5, maintained by the V-ATPase pump.

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V-ATPase

A proton pump that uses energy from ATP hydrolysis to pump hydrogen ions (H+) into the lysosomal lumen, creating its acidic environment.

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Acid Hydrolases

Enzymes that function best in acidic conditions, breaking down various macromolecules within lysosomes.

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SLC Transporters

A family of membrane proteins that transport specific molecules, like amino acids, across the lysosomal membrane.

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Amino Acid Sensing Machinery

A complex of proteins on the lysosomal surface, including SLC38A9, that detects luminal arginine levels and activates mTOR.

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mTOR

A protein kinase that plays a central role in controlling cell growth and metabolism, activated by amino acid sensing machinery.

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Nutrient Acquisition

The process of obtaining necessary nutrients from the environment, facilitated by lysosome solute efflux.

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Proton-Coupled Amino Acid Transporters

Transporters that move amino acids across the lysosomal membrane using the proton gradient created by V-ATPase.

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Autophagy Failure in Aging

The breakdown of cellular waste and damaged components becomes less efficient with age. This can lead to a buildup of toxic materials, reduced energy production, and an increased risk of disease.

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Lipofuscin Accumulation

A type of cellular waste product, also called 'age pigment', accumulates in lysosomes (recycling compartments) as we age. It can interfere with autophagy by preventing proper fusion and degradation of waste within the cell.

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Glucagon Signaling Decline

In older cells, the hormone glucagon, which normally promotes autophagy, becomes less effective at activating the process. This is because insulin signaling, which inhibits autophagy, remains elevated even in the absence of insulin.

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Mitochondrial Dysfunction

Inefficient autophagy contributes to the accumulation of damaged mitochondria, which are the powerhouses of cells. These damaged mitochondria produce harmful free radicals that can damage other cellular components.

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Increased Free Radical Production

Damaged mitochondria produce more reactive oxygen species (free radicals) that can harm proteins, DNA, and other cellular components. This oxidative stress contributes to the aging process.

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Autophagy and Longevity

Autophagy plays a vital role in promoting longevity by removing cellular debris, improving cellular health, and reducing the risk of age-related diseases.

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Fasting Mimicking Diet (FMD)

A diet that mimics the effects of fasting for several days, stimulating autophagy and promoting cellular regeneration. This has been shown to extend lifespan and improve health in mice.

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Regenerative Effects of FMD

FMD can increase stem cell numbers and promote the regeneration of various tissues, including bone, muscle, liver, brain, and immune cells.

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What is S6K1?

S6K1 is a kinase that promotes mRNA translation initiation by activating eIF4B, which aids the binding of the eIF4F complex to the 5' cap of mRNA.

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What is mTORC1?

mTORC1 is a protein complex that senses nutrients and energy levels to control protein synthesis. It's composed of important proteins like mTOR, raptor, and MLST8.

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How does mTORC1 get activated?

mTORC1 is activated by various signals, including insulin, growth factors, amino acids (like L-leucine), and mechanical stimuli. It is also sensitive to cellular energy levels and oxidative stress.

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How does mTORC1 affect translation?

mTORC1 phosphorylates 4EBP, causing it to detach from eIF4E. This allows the eIF4F complex to bind to the mRNA and initiate translation.

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What is the role of Rags in mTORC1 activation?

Rags are proteins that sense amino acid levels and recruit mTORC1 to the lysosome, where it becomes activated.

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How does mTORC1 influence ribosome biogenesis?

mTORC1 positively regulates ribosome production by promoting ribosomal RNA transcription and the synthesis of ribosomal proteins.

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What is the role of mTORC1 in mRNA translation?

mTORC1 regulates mRNA translation on ribosomes and can affect specific classes of mRNA transcripts based on their mRNA elements.

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How does mTORC1 affect overall protein synthesis?

mTORC1 stimulates protein synthesis by promoting translation initiation and ribosome production, increasing the overall rate at which cells make proteins.

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Study Notes

Dietary Cholesterol Movement

  • Cholesterol from the diet travels to the liver.
  • HDL (high-density lipoprotein) collects cholesterol from peripheral cells and returns it to the liver.
  • Cholesterol from cell membranes is loaded into HDL.
  • VLDL (very-low-density lipoprotein) releases triglycerides and remaining cholesterol to the liver or peripheral cells via LDL receptors.
  • Chylomicrons deliver dietary triglycerides to adipocytes and remnants are taken to the liver.

Cholesterol Feedback Inhibition

  • Cholesterol regulates its own production via feedback inhibition.
  • Feedback inhibition is a regulatory mechanism where the product of a metabolic pathway (in this case, cholesterol) inhibits an enzyme in the pathway, slowing the production of more product.

ERAD Pathway

  • ERAD (endoplasmic reticulum-associated degradation) is a cellular pathway for degrading misfolded or unassembled proteins in the endoplasmic reticulum (ER).
  • ERAD targets proteins to the cytosol for proteasomal degradation.
  • Proteins are recognized as aberrant by quality control receptors in the ER.
  • These misfolded proteins are then sorted to an ER membrane complex that includes adaptor proteins and an ERAD substrate.
  • This process often involves ubiquitination during transport across the ER.
  • Retrotranslocation complexes extract the ERAD substrate and prepare it for proteasomal degradation.

Proteolytic Pathways in Cells

  • The endosome-lysosome pathway targets extracellular and cell-surface proteins for degradation.
  • Intracellular organelles also enter this pathway.
  • The ubiquitin-proteasome pathway (UPS) targets cytoplasmic, nuclear, and ER proteins for degradation.
  • Mitochondria also have a proteolytic system.
  • Evidence suggests cooperation between these pathways.

Autophagy

  • Autophagy is a cellular process of degradation and recycling of cellular components.
  • Autophagy is regulated and can play a role in cell homeostasis.
  • Defects in autophagy have links to several human diseases, including neurodegeneration and cancer.
  • Macroautophagy, microautophagy, and chaperone-mediated autophagy are three common types.

Ubiquitin-Proteasome System (UPS)

  • The UPS is a cellular pathway for targeted protein degradation.
  • It involves ubiquitin, an enzyme called E1, E2, and E3 ligase, and finally, the proteasome.

Consequences of Autophagy Failure

  • Protein aggregates may accumulate
  • Organelle turnover is impaired
  • Free radicals may increase
  • Energetic compromise can result in the aging cells

Metabolic Health and Life Span

  • Promoting autophagy may improve metabolic health and lifespan.
  • Researchers have discovered that periodic fasting mimicking diets can extend lifespan in mice.

mTOR Regulates Cell Growth and Metabolism

  • mTOR plays a crucial role in regulating energy balance by controlling protein, lipid, and nucleotide synthesis, lysosome autophagy, and biogenesis.
  • mTORC1 and mTORC2 are the two complexes in the mTOR pathway.
  • mTORC1 and mTORC2 are regulated by a series of mechanisms.

Amino Acid Sensing and the Lysosome

  • Amino acid sensing (specifically arginine) is a crucial regulator of lysosomal function.
  • The activation of the Rag proteins (RagA/B/C/D) and SLC38A9 aminoacid transporter, which detects and relays arginine signals from the lysosome to the mTORC1 pathway directly.
  • mTORC1 is activated.

Ribosome Production and Regulation

  • mTORC1 positively regulates several steps in ribosome biogenesis, including rRNA transcription, ribosomal protein synthesis, and ribosome components.
  • Specific mRNAs can be regulated by mTOR.

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Week 6 Lecture 10 (2) PDF

Description

This quiz covers the important mechanisms of dietary cholesterol movement, feedback inhibition, and the ERAD pathway. Test your knowledge on how cholesterol is transported, regulated, and degraded in the body. Perfect for students studying biochemistry and cellular biology.

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