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Baby's first @biorxivpreprint:
LRH-1 #Nutrigenomics: The Provision of Lauric Acid Results in the Endogenous Production of the Liver Receptor Homolog-1 Ligand, Dilauroylphosphatidylcholine, and LRH-1 Transactivation.
Summary & story thread
! 1/ https://www.biorxiv.org/content/10.1101/2021.02.01.429240v1
LRH-1 #Nutrigenomics: The Provision of Lauric Acid Results in the Endogenous Production of the Liver Receptor Homolog-1 Ligand, Dilauroylphosphatidylcholine, and LRH-1 Transactivation.
Summary & story thread
! 1/ https://www.biorxiv.org/content/10.1101/2021.02.01.429240v1
This paper has been something of a labor of love (but mostly headaches &pandemics). I based it off of some interesting work from my current postdoc mentor's lab, that identified a "unique" phosphatidylcholine ligand for the orphaned nuclear receptor LRH1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150801/
Background: Nuclear receptors are these cool transcription factors in cells that bind to DNA and impact gene transcription. They're not unfamiliar to nutrition folks - many nuclear receptors are confer signals abt nutrient status (Vitamin D; Retinoic Acid Receptor to name a few)
There is a general hunt in the field for the compounds that bind to nuclear receptors, as these are major regulators of nuclear receptor function and consequently tissue specific and whole body metabolism/physiology. but the Lee et al paper didn't immediately link to nutrition.
fun note on the Lee et al paper: a friend in grad school invited me for dinner with a group of folks to practice her dep journal club presentation that was on this paper. I didn't read the paper b4,we spent most of the night not doing any work & I totally missed its significance
fast-forward a few months as a major transgenic 
pregnancy phenotyping study I was doing produced null results 11 days before my qualifying exams, I'm doomscrolling through some background literature on a possible new project,accidentally stumble onto the paper again & it clicks
pregnancy phenotyping study I was doing produced null results 11 days before my qualifying exams, I'm doomscrolling through some background literature on a possible new project,accidentally stumble onto the paper again & it clicks
Lee et al describe their screen & ID of a PC termed dilauroylphosphatidylcholine (DLPC) that, when provided, bound to the nuclear receptor LRH-1, increased its target gene expression&was antidiabettiic. But the authors note its unclear if its relevant to endogenous physio systems
Dilauroylphosphatidylcholine might look like gobbledeegook but to the nutrition oriented mind, it sort of screams diLAURoylphosphatidylcholine: a PC with 2x lauric acid, the dominant 12 carbon saturated fat in tropical oils like coconut, palm kernel & babasu oil.
The antidiabetic part also struck me because it's been noted for a while that coconut oil high fat diets don't induce the quintessential insulin resistance in rodents:
https://pubmed.ncbi.nlm.nih.gov/16720718/ https://diabetes.diabetesjournals.org/content/58/11/2547.full
https://pubmed.ncbi.nlm.nih.gov/16720718/ https://diabetes.diabetesjournals.org/content/58/11/2547.full
I quickly started googling to see if anyone had described DLPC endogenously yet but couldn't find it reported in any metabolomic databases. Which was consistent w lauric acid being low in culture medias, lab animal& western diets <- complicated by databases having fasted samples.
In another fateful occurrence, one of the GOAT LRH-1 researchers happened to be 1) collaborating on another project with one of my dissertation co-chairs; 2) visiting Cornell the next week. She confirmed that folks in the LRH1 field couldn't find DLPC endogenously anywhere.
So I set off to do most of the experiments in this preprint testing the super simple question: if I give it lauric acid (termed C12:0 throughout), will it make DLPC?
Every nutrition scientist's dream: test a substrate deficiency hypothesis
Every nutrition scientist's dream: test a substrate deficiency hypothesis
Fortunately I was already doing another project ( https://clinicaltrials.gov/ct2/show/NCT03194659) looking at the impact of dietary choline supplementation on PC's enriched with DHA & was able to adapt our LCMS methods to look for DLPC. and C12:0/coconut oil are very cheap.
So we measured DLPC after giving lauric acid to cells (Figure 1), animals acutely & chronically (Figure 2), and to humans in a randomized crossover feeding trials (Figure 3). And looked a bit at synthesis & metabolism dynamics with d9-methyl-choline in mice (Table 1).
After showing that DLPC could be made endogenously under a ton of diff circumstances after giving C12:0,I still wanted to know whether that DLPC was functionally doing anything. I played around w diff cell lines a bit &saw evidence of agonism but LRH1 in cell lines is very weird.
and now after (a clinical year and) an interrupted 1st yr in the postdoc, I wrapped up some ex vivo & in vivo C12:0 provision studies in hepatic LRH1 wildtype vs knockout mice showing that C12:0 provision increases LRH1 target genes (Figure 4), an effect lost in the KO.
There's some other data in there too: we tried feeding de novo lipogenic diets to see if DLPC could be produced endogenously, but didn't see this at any time point. We also fed 13C-C12:0 -only saw doubly labeled DLPC; to date,we can only see evidence of exogenous C12:0 -> DLPC
We ultimately conclude that we think the literature needs to look at the physiological and health effects of C12:0/lauric acid containing oils, with an eye towards things that LRH-1 impacts. There are some low hanging fruit targets.
For example, LRH-1 has well defined roles in regulating local glucocorticoid synthesis in the gut (IBD) & progesterone synth in the ovary (RPL). C12:0 is also high in mammalian milk, making us wonder about its role in early development. LRH1 GWAS: https://www.gwascentral.org/generegion/phenotypes?q=NR5A2&t=2&fpf=0&tpf=0&l=asd&r%5B%5D=&page=1&o=1&page_size=50&format=
Testing this potential will be tough though, like most nutrition topics. Key will be more tissue specific LRH-1 knockout mouse studies (homozygous is embryonic lethal), with enough funding (lol) to do dose-response studies and multiple isocaloric comparators (lolol).
Nutrition epi will be rough here. A lot of the better epi cohorts use FFQs, that don't explicitly list tropical oils. DLPC has a short half life so can't measure circulating easily. There is some epi to date- intakes are low, confounding potential is huge: https://link.springer.com/article/10.1007/s00394-018-1630-4
Human trials are more likely. There's already some evidence in lean healthy overfed adults that 12:0 rich diets preventing glucose handling/SI impairments compared to longer chain saturates. Of course no certainty here that this is related to LRH1. https://diabetes.diabetesjournals.org/content/70/1/91
More work is needed to be done to see if C12:0 rich feeding results in a LRH-1 sensitive biomarker - a possible candidate is serum bile acids, particularly cholic acid & its derivatives. And of course, this will all matter what is replaced/isocaloric comparator is chosen.
Lots of basic science work to be done here too - would love to know whether lauric -> DLPC involves nuclear PC synthesis; if PCTPs are involved; whether a Land's type cycle is required for synthesis as in lung surfactant PC16:0/16:0, how bioenergetics, disease states influence
But we feel confident in concluding from our available findings that C12:0 is pretty uniquely interesting & doing more than just serving as an energy source & influencing LDL/HDL. That alone is far from a reason to advocate eating a bunch but it opens up new lines of study!
fun topic for speculation - C12:0 is rich in tropical oils due to the presence of medium chain acyl ACP thioesterases, thought to have important structural roles for plants in the tropics. If humans evolved in tropical climates, might we have eaten a lot of C12:0 beyond infancy?
i've gotten a lot of questions about what intakes of C12:0 are relevant. this is tough to answer - intakes are everything from <1% kcals in western populations to >20% kcals in recent history in Pacific islands. What's the functional consequences of this?
