Summary 17032021

Regulation of glucose metabolism in the liver

The liver controls many pathways of glucose metabolism.

Biochemistry I

Paola Pimiento

References

Han, H., Kang, G., Kim, J. Choi, B. & Koo, S. (2016). Regulation of glucose metabolism from a liver-centric perspective. Experimental and Molecular Medicine, 48, e218.

Glucose synthesis from lactate, amino acids and glycerol.

Glycogen metabolism

Glycogenesis

Glycogenolysis

Key enzyme is glycogen synthase.

Key enzyme is glycogen phosphorylase.

It elongates the glycogen chains.

It transfers UDP-glucose to the existing glycogen chain.

It is inactivated by phosphorylation.

Done by serine/threonine kinases like:

Casein kinase 1

Protein kinase A (PKA)

Glycogen synthase kinase-3 (GSK3)

Akt

It phosphorylates and inactivates GSK3.

It is activated by insulin.

It is activated by:

High glucose 6-phosphate concentrations.

It allosterically activates the enzyme and increases its activity.

Protein phosphatase 1 (PP1)

By dephosphorylation.

It removes glucose molecules from the glycogen chain.

Leads to the generation of glucose 1-phosphate.

It is activated by:

Phosphorylation on its serine 14 residue.

PKA

It activates the glycogen phosphorylase kinase by phosphorylation.

That enzyme activates glycogen phosphorylase.

Stimulated by glucagon and its reaction cascade.

It is inactivated by:

PP1

It is stimulated by insulin to inactivate this enzyme.

Glycolysis

Critical for the breaking down of glucose to obtain energy.

It has rate limiting steps.

Glucokinase (GK)

Phosphofructokinase 1 (PFK1)

Phosphoenol liver-type pyruvate kinase (L-PK)

It catalyzes the reaction from glucose to glucose 6-phosphate.

It catalyzes the reaction that converts fructose 6-bisphosphate to fructose 1,6-bisphosphate.

It catalyzes the reaction that converts phosphoenolpyruvate to pyruvate.

Unlike hexokinase it is not inhibited by high levels of glucose 6-phosphate.

It is regulated by Glucokinase regulatory protein (GKRP).

In fasting state:

Binding of GK and GKRP is enhanced by fructose 6-phosphate.

In fed state:

GK is released from GKRP because of its competition with glucose.

It is allosterically inhibited by ATP and citrate.

It is allosterically activated by ADP and AMP.

Activated by insulin-dependent phosphorylation.

PFK2 can inhibit it by not producing fructose 1,6-bisphosphate.

The enzyme decreases that activity when there is glucagon-mediated activation of PKA and inactivation of its kinase portion.

It has both allosteric and post translational modification regulators.

It is allosterically activated by fructose 1,6-bisphosphate.

It is allosterically inhibited by ATP, Acetyl CoA and long chain fatty acids.

Alanine inhibits its activity.

Inhibited by glucagon activated PKA and its consecutive increase of cAMP inside the cell.

It is also activated by insulin-mediated phosphorylation.

It is regulated by transcriptional mechanisms as well.

These activate during fed state.

Activated by Sterol regulatory element binding protein 1c (SREBP 1c) and carbohydrate response element binding protein (ChREBP).

These also activate lipogenic activity.

Studies in mice suggest ChREBP is crucial in the control of metabolic disorders like hyperlipidemia, hyperglycemia, and hyperinsulinemia.

Gluconeogenesis

Induced by long fasting periods.

It can also be stimulated by epinephrine.

There are many enzymes that are key to this regulation like:

Pyruvate carboxylase

Fructose 1,6-bisphosphatase

Allosterically activated by mitochondrial Acetyl CoA.

Increased production of oxaloacetate.

It can be allosterically inhibited by Fructose 2,6-bisphosphatase.

This inhibits gluconeogenesis.

This regulation is bound to fasting and fed state.

It is also regulated by transcriptional factors.

CREB

Its activation leads to gluconeogenesis.

This signaling pathways is activated by glucagon and epinephrine.

CRTC2

Its activation leads to gluconeogenesis.

Studies in mice show its inactivation can lead to low plasma glucose levels and a higher insulin resistance.

FOXO1

Activated by the insulin/Akt pathway.

It is also regulated by HAT-dependent acetylation that inhibits its activity.

It is important for insulin-related suppression of gluconeogenesis.

PGC-1alpha

It is regulated by CRTC2-CREB-dependent mechanism.

It is key to keep prolonged gluconeogenesis in starving conditions.

It uses FOXO1 as a coactivator.

Its activity is affected by PRMT1.

It is also activated by fructose 1,6-bisphosphate.

Product of phosphofructokinase 2 (PFK2).