Visualizing thyroid hormone activity in cells: T3 and RT3 in context

I’ve recently been inspired by an visual of thyroid hormone cellular action published by Bianco and colleagues in September, 2019.

This visual has taught me a new way of seeing these hormones’ pathways of movement and activity in our bodies.

I’ve read Bianco’s article quite thoroughly in light of the image, and as a result I have been equipped with new lenses, like an updated eyeglass prescription: I can now see more clearly how T3 and RT3 interrelate.

The image also clarifies some of the common internet myths and misunderstandings about Reverse T3.

Well-meaning people have attributed to the hormone RT3 a “T3-blocking” function. But science shows that the T3-blocking function is largely performed by Deiodinase Type 3, the enzyme that makes T4 into RT3 and makes T3 into T2.

It’s more than a semantic distinction between “RT3 dominance” and “D3 dominance,” because D3 can still dominate in the body when RT3 hormone is low in blood.

“Seeing” thyroid hormones anew can shift one’s understanding of RT3 and thyroid hormone economy. It can enhance thyroid testing and dosing decisions in thyroid therapy.

• First I’ll talk about why there are two cells in Bianco’s 2019 image (Like a pair of glasses!).
• Then I’ll talk about the left half and right half in more detail.
• I’ll provide my own image of a cell and explain my edits.
• I’ll enter a discussion on various topics that arise from Bianco’s image & article

Vocabulary and abbreviations

• Deiodinase type 1, type 2, and type 3 are the set of three enzymes that convert thyroid hormones in the human body. They are abbreviated D1, D2, and D3.
• The genes responsible for these enzymes are DIO1, DIO2, and DIO3 (spelled d-i-o #)
• The gene name (DIO2) and the enzyme (D2) sometimes substitute for each other because increased DIO2 expression will lead to increased D2 enzyme activity.
• A “D2-expressing cell” is a cell that just happens to have D2 enzyme within it. I’ll use “D2-x cell” to abbreviate the “Deiodinase type 2 expressing cell”.

Need more basic knowledge first?

If you don’t feel confident with basic principles in thyroid hormone action, I recommend this new overview post intended to support and contextualize this one.

• The basics of thyroid hormone action, transport and conversion

Our blog also has many other posts on the topic of specific thyroid hormones. You can navigate posts using the “Categories” browser in the sidebar of the website.

Figure 1 from Bianco et al, 2019

Here’s the big, complex picture as a whole.

If it is too small for your screen, I’ll zoom in below — just scroll down.

(NOTE: Images and quotations are reproduced within Canadian and US copyright “fair dealing” and “fair use” for purposes of education and review: See copyright law info.)

There are actually three enzymes that convert thyroid hormones, not just two.

The image only portrays two of them, Deiodinase type 2 (D2) and Deiodinase type 3 (D3).

• In the left-hand cell, the D2 enzyme takes T4 and converts it to T3.
• In the right-hand cell, the D3 enzyme takes T4 and converts it to Reverse T3.
• In the right-hand cell, D3 also takes T3 and converts it into a form of T2.

Where’s the third type of cell?

The Deiodinase type 1 enzyme (not shown) plays a lesser, supportive role.

• In the D1-expressing cells (not shown), the D1 enzyme is located in and around the edge of the cell membrane, like the orange dots around the edge of the D3 cell.
• The visual model for D1 conversion activity would be more complex, if there was one. There just isn’t an image of the D1 expressing cell available because science hasn’t yet examined this conversion pathway thoroughly.
• D1 focuses on converting RT3 and T3-Sulfate, and we still know little about T3S.
• We know D1 also plays a supportive role converting T4 into both T3 and RT3, but it’s not yet understood what makes the enzyme choose to make T3 instead of RT3.

Some cells express D2. Others express D3.

• “D2 and D3 are usually not expressed together in the same cell” (Groeneweg, 2017), and this is reflected in Bianco’s image.

These two types of cells have complementary and opposing functions in our thyroid hormone economy.

• When DIO2 is downregulated in a given local tissue (or throughout the body), DIO3 is upregulated, and vice versa.

Their influence is like a see-saw. When one dominates, the other is suppressed.

In a healthy person with a normal thyroid, D2 and D3 are usually balanced throughout their body, yet are ready to respond and adjust to changes in thyroidal secretion rate, thyroid secretion ratio, and health and environmental conditions.

When the body or a local tissue is attempting to compensate for illness, damage, and/OR excess or low thyroid hormone, the deiodinases will become imbalanced by D3 dominance.

D2: LEFT side of image

When Free T4 enters a cell expressing D2, some of it gets converted to the active hormone T3.

Notice that the D2-expressing (D2-x) cells do not convert any T4 into Reverse T3.

T3 hormones from two origins are ushered into the nucleus where they can bind to the thyroid hormone receptors.

• locally converted T3 (blue dots labeled “T3[T4]”)
• circulating Free T3 from bloodstream (purple dots)

In more depth:

1. Circulating Free T3. Some T3 comes into the cell from bloodstream and is ushered into the cell. When FT3 levels are sufficient for health, a given % of receptors in the nucleus are occupied by circulating FT3. The organ or tissue DEPENDS on this baseline “income” much like a sufficient, regular salary enables financial health.
2. Locally converted T3. Some T3 is created in the cell as D2 converts it from FT4. The D2 enzyme in the cell attempts to “top up” the nuclear T3 receptor occupancy above the baseline by increasing or decreasing the local rate of T4-T3 conversion. In a financial metaphor, this is like interest you earn on investments when the interest rate continually fluctuates.

However, D2-converted T3 behaves very differently from D1-converted T3.

• The T3 we convert from T4 within a D2-x cell remains bound to the nuclear receptor for a longer time (“several hours”), and scientists think it’s because D2 enzyme is located so close to the nucleus.
• The T3 we convert from T4 within a D1-x cell (not shown in the image) remains bound to the receptor for less time (“~ 30 minutes”) before quickly exiting the cell to contribute to T3 circulation, likely because D1 enzyme is located just inside the cell membrane, close to where transporters enable hormones to exit the cell.
• The longer time spent in the nuclear receptor of D2-x cells adds up to a 6x greater potency / effect of T3 occupancy in the nuclei of D2 cells versus D1 cells.

The rate of D2’s conversion activity is regulated and limited. It depends largely on the supply of Free T4 (and its child-hormone RT3) entering the cell via transporters.

• To the degree that circulating FT4 levels are higher within reference range and beyond it, D2 molecules will become progressively inactivated by the process of ubiquitination. The rate of T4-T3 conversion will decrease. However, it will never entirely stop converting into T3 and ushering circulating FT3 to the nucleus.
• Conversely, when circulating FT4 levels are lower in reference or below it, D2 becomes reactivated and begins to dominate, converting a higher percentage of T4 into T3. The rate of T4-T3 conversion will increase in an effort to maintain local T3 and circulating T3. But there is a point past which D2 cannot compensate, otherwise hypothyroidism would be impossible.

D3: RIGHT side of image

When T4 & T3 enter a cell expressing D3, they both get inactivated simultaneously.

• These cells don’t just convert T4 into Reverse T3.
• They also convert T3 into T2, more specifically, 3,3′-T2 (Reverse T2)

Normally, D3 enzyme resides just inside the edge of the cell membrane.

But in states of illness (hypoxia, ischemia), D3 gathers around the nucleus of the cell to make sure that less T3 hormone reaches the nucleus.

• D3-x cells do their best to block T3 from reaching its receptors in their nucleus. This reduces the amount of T3 performing genetic signaling within this local tissue.
• D3-x cells also act as a “thyroid hormone sink” that removes some FT4 and FT3 from bloodstream circulation that could enter other cells.

My corrected & enhanced image of the D3-x cell

Even Bianco would acknowledge there’s an error in the image.

Bianco and team failed to show the exit of RT3 and T2 out of the cell and into the bloodstream, carried by the Thyroid Hormone Transporters (THTs). Instead, they show only two types of T3 hormone exiting the D3 cell. This makes no sense given Bianco’s other publications, citations, and the full text of their article, as I’ll explain.

Therefore, I’ve made my own version of the DIO3 expressing cell that creates Reverse T3, and I’ve explained the changes below.

Improvements:

1. Colors and shapes now distinguish T4 (blue) from its two T3 products (both pink).
2. Color distinguish RT3 (pink empty circle) from “Reverse” T2 (green) because they are two separate hormones and should not be merged into one dot.
3. No distinction is needed between two origins of T3 — there is only one T3 molecule. Compared to the D2-x cell, there is no locally-converted T3 product in this cell. Free T3 transported from blood is the only origin of T3 present in this cell, and it doesn’t matter where it originally comes from: Thyroidal secretion, hormone dosing, etc.
4. The nucleus should be less populated with T3 to signify that there’s small chance of T3 molecules getting past the D3 army when D3 is highly expressed in many cells in the body and FT3 concentrations are already lower in blood.
5. RT3 and T2 now exit the cell, as they should.

As for Correction # 5, The exit of T2 and RT3 from the cell are expressed in this older image from Bianco & Kim, 2006.

As you can see from the 2006 model, the grey circles representing hormones RT3 and T2 are exiting the cell. (I’m ignoring the left half of the image in this post.)

The main difference here in the 2006 image is that D2 is depicted in the same cell that expresses D3. That’s because as of 2006, it was not yet understood that some cells expressed D2 and others expressed D3.

Back to the 2019 image…

Bianco et al explain on page 1010:

“T3 production via D1 and D2 occurs inside cells, but T3 molecules eventually exit such cells via TH [Thyroid hormone] transporters mixing with the pool of circulating T3.

In contrast, D3-expressing cells function as sinks for T3 and T4, dampening local TH signaling and consuming circulating TH.”

If D3-x cells are “sinks” that “consume” circulating thyroid hormones, you have to have no T3, or hardly any T3, exiting the D3-x cell.

In addition, RT3 and T2 must exit to the degree that they are generated in the D3-x cell to maintain equilibrium between influx and efflux, otherwise you would have cells losing or gaining mass over time.

Without the 2-way function of THTs carrying Reverse T3 out of the cell, we would not have any Reverse T3 in bloodstream at all, because RT3 is only created from T4 hormone within cell membranes.

DISCUSSION

This post was extremely long, so I’ve broken it into 2 separate posts.

I engage in a lot of discussion of these D2 and D3 cell images and their implications for thyroid therapy here:

• Deiodinase Type 3 plays a T3-blocking function

REFERENCES

The reference list is found at the end of the Part 2 post, The basics of thyroid hormone action, transport and conversion.

Earlier posts on Reverse T3 and deiodinases

You may also be interested in…

• GRAPHIC and discussion: T3 Depletion
• Recovery from T3 depletion
• How the three deiodinases regulate T3
• Deiodinase type 3 and Reverse T3
• Interpreting Free T3 and Free T4 in therapy
• Do you have a Reverse T3 problem?
• Thyroid hormone conversion
• The Low T3 Syndrome in memes
• Ubiquitination: The glass ceiling of T4 monotherapy