# ApoB Structure and Function

**URL:** <https://discourse.peacefulscience.org/t/apob-structure-and-function/5443>\
**Category:** Conversation\
**Created:** [March 19, 2019, 4:05pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443 "2019-03-19T16:05:34Z")\
**Posts on this page:** 20\
**Page:** 1

<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 19, 2019, 4:05pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/1 "2019-03-19T16:05:35Z")

</div>

Behe’s book as resulted in a lot of attention being focused onto one gene: ApoB. I thought it might be useful for the scholars here at PS to do some background work on what ApoB does, what effects mutations may have, and possibly what effects the specific changes in the polar bear ApoB gene may have.

I found a useful review article:

> [@](#):
>
> Plasma lipoproteins are important determinants of atherosclerosis. Apolipoprotein (apo) B is a large, amphipathic glycoprotein that plays a central role in human lipoprotein metabolism. Two forms of apoB are produced from the _APOB_ gene by a unique posttranscriptional editing process: apoB-48, which is required for chylomicron production in the small intestine, and apoB-100, required for VLDL production in the liver. In addition to being the essential structural component of VLDL, apoB-100 is the ligand for LDL-receptor-mediated endocytosis of LDL particles.  
> [Lipid Disorders and Mutations in the APOB Gene | Clinical Chemistry | Oxford Academic](http://clinchem.aaccjnls.org/content/50/10/1725.long)

It would appear that ApoB has two main functions: getting cholesterol into the blood stream and getting it out of the blood stream. Therefore, high or low levels of lipids in the blood stream can be affected by lipid production and lipid clearance. I have only briefly skimmed the abstract of the paper and thought it would be a great topic for the scholar forum.

Interestingly, ApoB is found in two isoforms through post-transcriptional modification: apoB-48 and apoB-100. It would appear that the smaller isoform is responsible for transferring dietary lipids into the blood stream. This may hold a key for understanding possible active sites for lipid production and lipid clearance, and the possible effects of certain mutations in those domains.

For now, I don’t think we need to specifically address Behe’s larger arguments. Rather, we could narrowly focus on understanding the role of ApoB in lipid metabolism.

---

<div class="post-metadata">

**Author:** ![cwhenderson](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/cwhenderson/32/72_2.png) [@cwhenderson](https://discourse.peacefulscience.org/u/cwhenderson)\
**Post date:** [March 19, 2019, 7:31pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/2 "2019-03-19T19:31:40Z")

</div>

One of the really interesting things about the isoforms is that the smaller apoB-48 is a product of specific RNA editing that introduces a premature stop codon. It appears that mutations affecting the C-terminal portion of the protein would be much more of an issue for the apoB-100 vs the apoB-48, resulting in a possible effect on LDL uptake, without significant effect on chylomicron production. I haven’t done any investigating yet, but it would be interesting to see where the mutations have occurred in the polar bear version of the gene.

---

<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 19, 2019, 8:31pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/3 "2019-03-19T20:31:50Z")

</div>

> [@cwhenderson](#):
>
> One of the really interesting things about the isoforms is that the smaller apoB-48 is a product of specific RNA editing that introduces a premature stop codon.

I found that interesting as well. I had to go back and change posttranslational to posttranscriptional in the opening post because I had assumed proteolytic cleavage was responsible for the isoforms. Goes to show what assuming things gets you.

> [@cwhenderson](#):
>
> It appears that mutations affecting the C-terminal portion of the protein would be much more of an issue for the apoB-100 vs the apoB-48, resulting in a possible effect on LDL uptake, without significant effect on chylomicron production. I haven’t done any investigating yet, but it would be interesting to see where the mutations have occurred in the polar bear version of the gene.

That’s my read as well. Here is the figure from the polar bear paper:

 ![image](https://us1.discourse-cdn.com/flex016/uploads/peacefulscience/original/2X/6/6c641bf3cb5e6b9ba2477b366464b097d25e2cab.jpeg)

> [@](#):
>
> [Fig. 5](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089990/figure/F5/)
> 
> **The apoB and LYST protein sequences**
> 
> The distribution of fixed non-synonymous polar bear mutations (blue arrows) compared to the brown bear, using the giant panda sequence as an outgroup. ( **A** ) Mutations predicted to affect protein structure based on apoB alignments across 20 vertebrate species, using the SIFT algorithm (Sim et al., 2012), are indicated with hollow circles on arrows. The grey curve shows the cubic smoothing spline of the amino acid conservation scores; higher scores indicate higher conservation across 20 vertebrate species. The x-axis shows the amino acid position from the N-terminal, the five domains are based on the human apoB sequence ([Prassl and Laggner, 2009](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089990/#R37)). ( **B** ) The same representation as in panel A, but for the LYST protein sequence. The domains are based on [[InterPro](http://www.ebi.ac.uk/interpro/protein/LYST_HUMAN)]. ( **C** ) Mapping of polar bear-specific substitutions and Chediak-Higashi syndrome causing variants on the protein structure of LYST N-terminal domain.  
> [Liu et al. (2014)](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089990/)

For reference, human apoB-100 is 4,536 amino acids long while apoB-48 is comprised of the first 2,152 amino acids (i.e. the N-terminal portion). The mutations listed in the figure are only those expected to affect protein structure according to Polyphen.

At first glance, there could be changes in both functions: transfer of dietary lipids into the blood stream and clearance of serum lipids into cells. The greatest danger that I see is assuming every mutation was selected for. If I am getting my population genetics right, some neutral mutations could have hitchhiked along with the beneficial mutations.

---

<div class="post-metadata">

**Author:** ![swamidass](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/swamidass/32/3_2.png) [@swamidass](https://discourse.peacefulscience.org/u/swamidass)\
**Post date:** [March 19, 2019, 9:14pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/4 "2019-03-19T21:14:33Z")

</div>

> [@T\_aquaticus](#):
>
> If I am getting my population genetics right, some neutral mutations could have hitchhiked along with the beneficial mutations.

That seems correct. It is also possible they are epistatically linked: more than one of them together is required for the function.

---

<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 19, 2019, 9:56pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/5 "2019-03-19T21:56:24Z")

</div>

As an aside . . .

If memory serves, @Mercer is familiar with the molecular biology of cardiomyopathies, so there might be something worth pursuing in this section of the polar bear paper:

> [@](#):
>
> We find that nine out of the top 16 genes showing the strongest evidence of positive selection in polar bears are directly related to heart function in humans (Table 1). Mutations in all nine genes, including APOB, are associated with either atherosclerosis or cardiomyopathy in humans and other mammalian model organisms. TTN encodes Titin, an abundant protein of striated muscle, which includes cardiac muscle tissue; mutations in TTN are associated with familial dilated cardiomyopathy (Herman et al., 2012). XIRP1, also known as Cardiomyopathy-associated protein 1, is associated with the development of cardiac muscle cells (van der Ven et al., 2006). ALPK3 encodes a kinase and plays a role in cardiomyocyte differentiation; knockout genes in mice show both hypertrophic and dilated forms of cardiomyopathy (Van Sligtenhorst et al., 2012). VCL encodes vinculin, a cytoskeletal protein associated with cell-cell and cell-matrix junctions, which is also the major talin-binding protein in platelets. Defects in VCL are associated with dilated cardiomyopathy in humans (Olson et al., 2002). EHD3 encodes a class of cardiac trafficking proteins and plays a role in endocytic transport (Galperin et al., 2002). Regulation of EHD3 plays a role in a molecular pathway related to heart failure (Gudmundsson et al., 2012). ARID5B is involved in pathogenesis of atherosclerosis and adipogenesis (Wang et al., 2012). ABCC6 is associated with transport of molecules across membranes and is associated with premature atherosclerosis (Trip et al., 2002), and CUL7 plays a role in vascular morphogenesis (Arai et al., 2003).  
> [Liu et al. (2014)](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089990/)

---

<div class="post-metadata">

**Author:** ![cwhenderson](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/cwhenderson/32/72_2.png) [@cwhenderson](https://discourse.peacefulscience.org/u/cwhenderson)\
**Post date:** [March 20, 2019, 2:59am UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/6 "2019-03-20T02:59:41Z")

</div>

> [@T\_aquaticus](#):
>
> If memory serves, @Mercer is familiar with the molecular biology of cardiomyopathies, so there might be something worth pursuing in this section of the polar bear paper:

Yes, this was interesting, too. I haven’t read up thoroughly, but I don’t recall the cardiac function genes coming up earlier. Presumably, cardiac function would need to increase for the environment and the greater need for swimming efficiency. Behe would have a hard time arguing that these mutations were “breaking” their genes.

---

<div class="post-metadata">

**Author:** ![Mercer](https://avatars.discourse-cdn.com/v4/letter/m/e274bd/32.png) [@Mercer](https://discourse.peacefulscience.org/u/Mercer)\
**Post date:** [March 20, 2019, 5:14am UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/7 "2019-03-20T05:14:36Z")

</div>

> [@T\_aquaticus](#):
>
> If memory serves, @Mercer is familiar with the molecular biology of cardiomyopathies, so there might be something worth pursuing in this section of the polar bear paper:

I doubt that any of them are LOF.

It looks like the authors didn’t bother to pursue any of them beyond looking them up in OMIM, given the laundry-list style they used.

What’s far more important IMO is functional assays on the polar bear APOB alleles.

---

<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 21, 2019, 7:51pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/8 "2019-03-21T19:51:11Z")

</div>

I don’t know if this was mentioned in previous threads, but polar bear cholesterol levels are extremely high:

> [@](#):
>
> Cholesterol levels in blood plasma of polar bears are extreme (e.g. [Ormbostad, 2012](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089990/#R32)); in humans, elevated cholesterol levels are a major risk factor for the development of cardiovascular disease ([Cannon et al., 2010](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089990/#R6)). It remains an enigma how polar bears are able to deal with such lifelong elevated levels of cholesterol.  
> [Lui et al. (2014)](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089990/)

This would seem to indicate that apoB-48 is fully functional since that portion of the protein is responsible for transporting lipids from the intestine into the blood stream and lymph. If apoB-48 had lost function then we would expect to see hypocholesteremia.

But what about hypercholesterolemia (i.e. high cholesterol in blood stream)? The review article lists four mutations in humans that interfere with the LDL binding domain: R3500Q, R3500W, R3480W, and R3531C. After a little digging over at Uniprot and a quick alignment, here is the region of the human and polar bear proteins covering those arginines:

```auto
Bear 3361 DIKGSVFSREYSGTIASEASTYLNSKSTRSSVKLQGASKVDDIWNLEVKENFAGEATLQR 3420
             D+KGSV SREYSGTIASEA+TYLNSKSTRSSVKLQG SK+DDIWNLEVKENFAGEATLQR
Human 3499 DVKGSVLSREYSGTIASEANTYLNSKSTRSSVKLQGTSKIDDIWNLEVKENFAGEATLQR 3558

Query 3421 IYGIWEHNTKNNLQLEGFFSSSGEHTSKATLELSPWKMSALIQVHASQPSSLLEINYLGQ 3480
             IY +WEH+TKN+LQLEG F ++GEHTSKATLELSPW+MSAL+QVHASQPSS + LGQ
Sbjct 3559 IYSLWEHSTKNHLQLEGLFFTNGEHTSKATLELSPWQMSALVQVHASQPSSFHDFPDLGQ 3618
```

The numbering is a bit off, so R3500 is the R at RSSVKL. In fact, all three R’s in that top row are involved in the mutations related to hypercholesterolemia in humans, and all three R’s are not mutated in the polar bear gene. Therefore, the high levels of cholesterol in the polar bear are not due to known mutations in humans.

At first glance, there is no evidence as of yet that any function has been lost in polar bear apoB, but further investigation is needed. Two of the remaining questions are why polar bear cholesterol levels are so high, and how are they able to tolerate these high levels without suffering from atherosclerosis.

BIG EDIT!!  
There is also an H3543Y mutation in humans related to high cholesterol, and the same H is an N in polar bears. This definitely deserves more investigation. I somehow missed this on the first go through.

---

<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 21, 2019, 8:13pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/9 "2019-03-21T20:13:11Z")

</div>

Since the last post focused on the human and polar bear comparison, it is probably important to compare the same region between brown bears and polar bears:

```auto
Polar 3364 GSVFSREYSGTIASEASTYLNSKSTRSSVKLQGASKVDDIWNLEVKENFAGEATLQRIYG 3423
             GSVFSREYSGTIASEASTYLNSKSTRSSVKLQGASKVDDIWNLEVKENFAGEATLQRIYG
Brown 3372 GSVFSREYSGTIASEASTYLNSKSTRSSVKLQGASKVDDIWNLEVKENFAGEATLQRIYG 3431

Query 3424 IWEHNTKNNLQLEGFFSSSGEHTSKATLELSPWKMSALIQVHASQPSSLLEINYLGQEVS 3483
             IWEHNTKNNLQLEGFFSSSGEHTSKATLELSPWKMSALIQVHASQPSSLLEINYLGQEVS
Sbjct 3432 IWEHNTKNNLQLEGFFSSSGEHTSKATLELSPWKMSALIQVHASQPSSLLEINYLGQEVS 3491
```

This is the same region where several mutations in humans are responsible for high cholesterol. In the case of the polar and brown bear, they have identical amino acid sequences in this region. Therefore, if there were any “damaging” mutations then they originated in the ancestor of both brown bears and polar bears. This would include the possible mutation at the orthologous H3543 position from the human protein.

---

<div class="post-metadata">

**Author:** ![Mercer](https://avatars.discourse-cdn.com/v4/letter/m/e274bd/32.png) [@Mercer](https://discourse.peacefulscience.org/u/Mercer)\
**Post date:** [March 21, 2019, 8:17pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/10 "2019-03-21T20:17:49Z")

</div>

> [@T\_aquaticus](#):
>
> Two of the remaining questions are why polar bear cholesterol levels are so high, and how are they able to tolerate these high levels without suffering from atherosclerosis.

It may be as simple as not living long enough.

> [@T\_aquaticus](#):
>
> There is also an H3543Y mutation in humans related to high cholesterol, and that mutation is different in polar bears.

How can it be “that mutation” if it’s different?

---

<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 21, 2019, 8:24pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/11 "2019-03-21T20:24:07Z")

</div>

> [@Mercer](#):
>
> It may be as simple as not living long enough.

That doesn’t seem to be the case:

> [@](#):
>
> _ **Is atherosclerosis a disease affecting all animals or only certain animals?** _
> 
> Atherosclerosis affects only herbivores. Dogs, cats, tigers, and lions can be saturated with fat and cholesterol, and atherosclerotic plaques do not develop ([1](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1312295/#B1), [2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1312295/#B2)). The only way to produce atherosclerosis in a carnivore is to take out the thyroid gland; then, for some reason, saturated fat and cholesterol have the same effect as in herbivores.
> 
> . . .
> 
> _ **Is atherosclerosis a consequence of aging and therefore a degenerative disease?** _
> 
> No. When I was in medical school, I was taught that atherosclerosis was a disease of aging and that it was to be expected as we got older. It is true that symptomatic and fatal atherosclerosis is usually a problem of older people. But, not too old. Patients with homozygous familial hypercholesterolemia, however, may have lipid plaques in their arteries at the time of birth.
> 
> It appears that atherosclerosis requires certain serum cholesterol levels over certain periods of time. Therefore, if one has a serum total cholesterol of 1000 mg/dL, death usually occurs by age 15 (without lipid-lowering therapy).
> 
> [Twenty questions on atherosclerosis - PMC](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1312295/)

It is interesting that humans don’t tolerate higher levels of cholesterol in the same way herbivores don’t.

> [@Mercer](#):
>
> How can it be “that mutation” if it’s different?

That is probably the result of multiple edits. Will fix.

---

<div class="post-metadata">

**Author:** ![Mercer](https://avatars.discourse-cdn.com/v4/letter/m/e274bd/32.png) [@Mercer](https://discourse.peacefulscience.org/u/Mercer)\
**Post date:** [March 21, 2019, 8:27pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/12 "2019-03-21T20:27:43Z")

</div>

> [@T\_aquaticus](#):
>
> That doesn’t seem to be the case:

Thanks. Even more simple, then!

Still, the way forward is to assay the function of the mutant ApoEs.

---

<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 21, 2019, 9:05pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/13 "2019-03-21T21:05:48Z")

</div>

Falling further down the rabbit hole:

So what are the cholesterol levels in polar bears, and in brown bears for that matter?

Brown bears: 7.89 ± 1.96 mmol/L (11.08 ± 1.04 mmol/L while hibernating)  
[ref](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439871/)

Polar bears: females (median): 8.58 ± 1.31 mmol/L, males: 6.61 ± 2.06 mmol/L  
[ref](https://brage.bibsys.no/xmlui/bitstream/handle/11250/245022/536490_FULLTEXT01.pdf?sequence=2&isAllowed=y)

For reference, it is suggested that humans have less than 200 mg/dL cholesterol which is 5.5 mmol/L. Hibernating brown bears have twice that level, while active brown and polar bears are about 50% above that (i.e. 300 mg/dL).

---

<div class="post-metadata">

**Author:** ![Rumraket](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/rumraket/32/9328_2.png) [@Rumraket](https://discourse.peacefulscience.org/u/Rumraket)\
**Post date:** [March 22, 2019, 10:43am UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/14 "2019-03-22T10:43:20Z")

</div>

On a related note, how does dietary fat content affect cholesterol levels? Presumably if you eat lots of fat, your cholesterol levels should go up because that’s one of the functions of cholesterol, to transport dietary fatty acids?

---

<div class="post-metadata">

**Author:** ![AndyWalsh](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/andywalsh/32/506_2.png) [@AndyWalsh](https://discourse.peacefulscience.org/u/AndyWalsh)\
**Post date:** [March 22, 2019, 2:48pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/15 "2019-03-22T14:48:24Z")

</div>

Well, I’ve certainly learned a lot from this thread about lipid metabolism.

Given that carnivores tolerate higher levels of circulating cholesterol, are the human and mouse studies of _APOB_ mutations even relevant to brown and polar bears?

Also, I got curious about the diet of brown bears and polar bears, and found this paper:

> **[Macronutrient optimization and energy maximization determine diets of brown...](https://academic.oup.com/jmammal/article/95/1/160/922646)**
>
> Abstract. Many animals consume mixed diets that maximize their fitness by optimizing macronutrient intake. We tested whether brown bears (Ursus arctos), genera

In addition to the research on brown bear diet selection, it includes some discussion of the literature on brown bear and polar bear diets, as well as the diets of other bears and other carnivores. They note that brown bears themselves have a high lipid diet relative to other carnivores. They also note that the literature on polar bear diet is not clear cut. So perhaps the diets and lipid metabolisms of brown bears and polar bears are not so drastically different?

Of course, we are still left with the observation that _APOB_ shows evidence of positive selection in polar bears. Perhaps it is still related to diet. My sense from the brown bear paper is that they may choose a high lipid diet possibly similar to polar bears’ (a) if it is available and (b) depending on one’s reading of the polar bear literature. Still, in the wild there may still be meaningful differences if polar bears only have high lipid options while brown bears have a more varied diet with lipid content changing based on availability and timing relative to hibernation. But I’m also wondering if hibernating/not hibernating is a bigger difference than diet between brown bears and polar bears, and if that has anything to do with the _APOB_ differences given that circulating cholesterol is higher in hibernating brown bears than in polar bears.

---

<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 22, 2019, 4:03pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/16 "2019-03-22T16:03:10Z")

</div>

> [@AndyWalsh](#):
>
> Given that carnivores tolerate higher levels of circulating cholesterol, are the human and mouse studies of _APOB_ mutations even relevant to brown and polar bears?

I think the studies on mice and humans are of limited value. The elevated levels of circulating cholesterol seem to be a shared feature in bears and aren’t a result of polar bear specific mutations.

As you mention, there is a strong signal of selection in polar bear ApoB. Given the comparable levels of circulating cholesterol in brown and polar bears, I don’t think it has anything to do with the prevention of atherosclerosis. Like you, I am leaning towards adaptations in lipid processing, perhaps related to the higher levels of mammalian fat in the polar bear diet. I could be wrong, but I think high lipid diets in brown bears are usually from fish fat. If they are hunting down mammalian prey they are going to be species like deer which are low in fat.

> [@AndyWalsh](#):
>
> But I’m also wondering if hibernating/not hibernating is a bigger difference than diet between brown bears and polar bears, and if that has anything to do with the _APOB_ differences given that circulating cholesterol is higher in hibernating brown bears than in polar bears.

The polar bear study didn’t measure circulating cholesterol in hibernating polar bears. For the moment, I think it would be safest to assume that the levels are similar in hibernating polar and brown bears.

As an aside, I certainly wouldn’t volunteer to be the person hunting down hibernating polar bears and drawing their blood.

---

<div class="post-metadata">

**Author:** ![AndyWalsh](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/andywalsh/32/506_2.png) [@AndyWalsh](https://discourse.peacefulscience.org/u/AndyWalsh)\
**Post date:** [March 22, 2019, 4:16pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/17 "2019-03-22T16:16:57Z")

</div>

> [@T\_aquaticus](#):
>
> I could be wrong, but I think high lipid diets in brown bears are usually from fish fat.

That makes sense. In the paper I linked above, the brown bears had options of salmon oil, and beef fat and pork fat as lipid sources, but that was in a controlled setting.

> [@T\_aquaticus](#):
>
> As an aside, I certainly wouldn’t volunteer to be the person hunting down hibernating polar bears and drawing their blood.

Especially since polar bears don’t hibernate like brown bears. They don’t become dormant, although they do go through metabolism changes.

---

<div class="post-metadata">

**Author:** ![Rumraket](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/rumraket/32/9328_2.png) [@Rumraket](https://discourse.peacefulscience.org/u/Rumraket)\
**Post date:** [March 22, 2019, 5:30pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/18 "2019-03-22T17:30:49Z")

</div>

> [@T\_aquaticus](#):
>
> As you mention, there is a strong signal of selection in polar bear ApoB. Given the comparable levels of circulating cholesterol in brown and polar bears, I don’t think it has anything to do with the prevention of atherosclerosis. Like you, I am leaning towards adaptations in lipid processing, perhaps related to the higher levels of mammalian fat in the polar bear diet.

I’ve been thinking the same thing. If the polar bear diet, because nothing else is available, has much more fat in it compared to the average brown bear diet, it would make sense that everything related to fat processing is under selection to improve.

In the arctic every fraction of a calorie potentially matters, probably more-so than it does for brown bears. That implies selection to improve fat uptake into blood through the gastrointestinal wall(let nothing go to waste), which probably partially involves improving fat transport through the bloodstream, improve fat storage (get it into cells), and improve the capacity to turn it into energy to power metabolism and muscular activity. Such adaptation could easily go beyond mutations in ApoB ofc.

> I could be wrong, but I think high lipid diets in brown bears are usually from fish fat. If they are hunting down mammalian prey they are going to be species like deer which are low in fat.

It might be worth noting that seal and whale fatty acid constituents is actually significantly more like the fatty acid contents found in fish, and quite unlike the fatty acid distribution found in terrestrial mammals like pork and beef meats.

---

<div class="post-metadata">

**Author:** ![AndyWalsh](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/andywalsh/32/506_2.png) [@AndyWalsh](https://discourse.peacefulscience.org/u/AndyWalsh)\
**Post date:** [March 22, 2019, 8:26pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/19 "2019-03-22T20:26:27Z")

</div>

I haven’t had a chance to go through it all, but here is another paper (also from 2014) comparing the genomes of polar bears and brown bears.

> **[Polar Bears Exhibit Genome-Wide Signatures of Bioenergetic Adaptation to Life...](https://academic.oup.com/gbe/article/6/2/433/536899)**
>
> Abstract. Polar bears (Ursus maritimus) face extremely cold temperatures and periods of fasting, which might result in more severe energetic challenges than th

---

<div class="post-metadata">

**Author:** ![T\_aquaticus](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/t_aquaticus/32/1249_2.png) [@T\_aquaticus](https://discourse.peacefulscience.org/u/T_aquaticus)\
**Post date:** [March 22, 2019, 9:26pm UTC](https://discourse.peacefulscience.org/t/apob-structure-and-function/5443/20 "2019-03-22T21:26:27Z")

</div>

I was looking to see if there was any findings related to fatty acid metabolism. This is the best I could find:

> [@](#):
>
> BAT [brown adipose tissue] is the primary site for adaptive thermogenesis. BAT is present in small mammals, such as rodents, and it has been demonstrated that an increase in UCP1 synthesis in BAT plays a key role in thermogenesis for hibernating small mammals occupying colder climates (Milner et al. 1989; Li et al. 2001; Yan et al. 2006). Increased mitochondrial activity may be an adaptation for quickly increasing and maintaining body temperature above lower limits during hibernation (Boyer and Barnes 1999; Lowell and Spiegelman 2000). In hibernating Arctic ground squirrels, expression of genes related to fatty acid catabolism and gluconeogenesis were increased in BAT, and it was suggested that these processes provide the energy to sustain adaptive thermogenesis or other high energy organs, like the brain (Yan et al. 2008). Glycerol, which arises from the breakdown of triglycerides, provides the substrate for gluconeogenesis, and thus can supply additional energy for increased thermogenesis (Yan et al. 2008). Increased expression of genes in the gluconeogenesis pathway, including PCK1, a main control point for the pathway, has also been found in hibernating black bears (Fedorov et al. 2011).
> 
> In larger mammals, BAT is present at birth but becomes sparse during development, and it has been suggested that BAT may be lacking in adult bears (Davis et al. 1990; Jones et al. 1999). However, thermogenesis has also been found to occur in white adipose tissue (Ye et al. 2013) and may potentially occur in muscle through more complex mechanisms (Wu et al. 1999; Lowell and Spiegelman 2000; Meyer et al. 2010). Interestingly, our analyses identified five genes related to gluconeogenesis that are potentially under positive selection in polar bears, including _PCK1._ If adaptive thermogenesis does occur in polar bears, and is fueled by gluconeogenesis similar to Arctic ground squirrels, it would not be surprising for genes in the gluconeogenesis pathway to be under selection, because the diet of polar bears is composed primarily of blubber and is essentially devoid of any substantial source of carbohydrates (Ramsay and Hobson 1991; Grahl-Nielsen et al. 2003). Recent work suggests that gluconeogenesis does increase in mice fed a high-fat diet (Obici et al. 2012). If polar bears utilize adaptive thermogenesis, it is possible that regulation of NO concentrations provides a mechanism to control energy balance at different times of the year and in response to individual needs. When polar bears have relatively more abundant food supplies, they could utilize heat production through thermogenesis to maintain their body temperature. During the summer, when temperatures are warmer and prey are less abundant, adaptive thermogenesis would not be necessary, thus allowing polar bears to minimize their energy expenditures and retain more of their fat reserves.

So there is some evidence of positive adaptation related to lipids. However, big data papers like this one often create more questions than answers. Another massive rabbit hole would be to look at NO regulation of lipid metabolism in the liver and possible contributions from ApoB. As usual, you go looking for a simple answer and find 10 complex questions.