Integrated metabolism & disease pathogenesis

Question 1

What is interconnected metabolism?

Answer 1

Interconnectedness of various metabolic pathways in the body and how they work together to maintain energy homeostasis and overall metabolic balance.
-Metabolic processes interact and influence eachother in a coordinated manner, they do not function in isolation.

Question 2

How do cancer cells rewire metabolism to promote tumorigenesis? (In CAC and glycolysis)

How do cancer cells affect ChREBP, NRF2 and HIF-1a?

What does chemotherapy try to do?

Answer 2

In CAC:
Glutamate -> a-ketoglutarate
a-ketoglutarate pool split in 2
1. a-ketoglutarate -> succinate -> OAA -> nucleotide biosynthesis
2.a-ketoglutarate -> iconitate (cancer biomarker) + citrate -> acetylCoA -> exported for lipogenesis (cell proliferation)

In glycolysis:
Diverts G6P towards PPP to support nucleotide synthesis
Upregulates glycolysis to produce lactate for tumor proliferation.

ChREBP: overstimulated to increase lipogenesis and cholesterogenesis

HIF-1a: overstimulated to increase glycolysis

NRF2: overstimulated to increases oxidative stress prevention (avoidance of cell death)

Chemotherapy: increases oxidative stress (increased ROS) to trigger cancer cell death.

Question 3

What metabolic effects would the increased expression of UPC3 have on an obese individual?

What does this mean for obesity treatment?

Answer 3

UPC3: uncoupling protein 3, present in muscle fiber.

Increased proton leak, without generation of ATP but rather generation of heat.
-Increased expenditure due to increased metabolic rate in attempt to compensate for loss of ATP production.

UPC3 is potentially a solution to obesity treatment if it can be upregulated. UPC1 in brown fat too.