SweetSue's Class Notes

[SweetSue]

Ok.... she’s speaking to professionals about medicine. I concede. There’s no one better. I love that she’s such a data geek. Lol!

However......all around the world are home healers using cannabis with a much more casual approach and getting marvelous results. It’s possible to home-medicate and not be stoned. This doesn’t have to be rocket science with the inflated price of lab testing.

In the same way that she’s disturbed that Bayer brought us single-molecule medicine I’m disturbed by this push to make cannabis be strictly controlled.

For some reason when I listen to this woman I respect so much I hear derision for those of us out here in the trenches who made it work in our kitchens and helped our loved ones without the assistance or support of the medical community.

A community that could stop this madness tomorrow if they were serious about healing and science.

 

[SweetSue]

Her message was dosing cannabis accurately and consistently as a medicine.

I realized listening to the end that it’s my basic mistrust of the medical profession getting in the way. I know we have to bring them into the picture, but to be honest I feel like they’ve been a big part of the problem, and I’m a bit unhappy that they’re benefiting financially from prohibition being relaxed and eventually eliminated.

It irritates me that they’re not making more of an effort to educate themselves. Reminds me of district attorneys who have to release those falsely imprisoned but who steadfastly refuse to admit they’d made any mistake. You screwed up big time. Own up and let’s move on. Together.

Ok.... notes:

Building an effective regimen in Mara’s world relies on
* testing so you know what’s in there
To which I find myself asking who gets hurt if you don’t know precisely what’s in there? Barring the extreme case when it does matter I don’t see the great danger in winging it.
* thorough patient intake (they do over 300 points with their patients - whew!)
* consistent plant-based medicines
* patient feedback

Mara stated that 75% of their patients wouldn’t be alive today without THC in the regimen
- It’s not a case of CBD is medicine and THC is not. They’re both medicine.

The best chemovars for medicines combine both uplifting and relaxation.

Using mg/kg dosing is totally ineffective with cannabis therapeutics
- no two patients will process cannabis in the same way
- no 2 medicines will express the exact same way
- younger patients require higher doses
There’s a theory afloat that youngsters have lower receptor concentrations than adults, that they increase in availability as we mature into adulthood. Just a theory I haven’t chased down yet.

Going forward it’d be nice to see
* regulation of professionally dispensed cannabis medicines
* standardization of plant-based cannabis medicines
* more research, particularly in observational studies

Justin had an observation on the earlier video that cannabis therapeutics for cancer was an inclusive approach. “When you show up, when you’re part of the healing, the human body is capable of amazing things.”

 

[SweetSue]

Ahhh....I love studying.

 

[SweetSue]

Back to the Carn

• SweetSue
• Aug 27, 2018

 

[SweetSue]

Bioavailability, in our discussions, is the amount of the cannabis you took that was actually available for your cells to use.

A lipoprotein is a biochemical assembly whose purpose is to transport hydrophobic lipid (a.k.a. fat) molecules in water, as in blood or extracellular fluid. ... Proteolipids are a different kind of protein-lipid - Wikipedia

Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).
Elmes MW, et al. J Biol Chem. 2015.
Show full citation
Abstract
Δ(9)-Tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex. Although it is known that these hydrophobic compounds can be transported in blood by albumin or lipoproteins, the intracellular carrier has not been identified. Recent reports suggest that CBD and THC elevate the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance. Fatty acid-binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH). By computational analysis and ligand displacement assays, we show that at least three human FABPs bind THC and CBD and demonstrate that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption. Using computational molecular docking and site-directed mutagenesis we identify key residues within the active site of FAAH that confer the species-specific sensitivity to inhibition by CBD. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. These data shed light on the mechanism of action of CBD in modulating the endocannabinoid tone in vivo and may explain, in part, its reported efficacy toward epilepsy and other neurological disorders.


“Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption.”

Not really sure why that jumped out at me, but it was loud enough that I copied it. Hmmmm.....

 

[SweetSue]

We know very little about all the rest of the endocannabinoids. Man! What an exciting time to be alive!

We barely know the phytocannabinoids. The major ones, yes, but the minor ones are just beginning to be explored. But endocannabinoids.....whew! I’ll have no lack of things to study.

I gotta make sure people know I’m no expert, just a curious woman willing to talk out loud.

 

[Amy Gardner]

Great video & reference Sue, thanks!

 

[Tennessee Tim]

You hit the nail on the head in regards to testing, versus home remedy! I wish I could have all my meds tested, however I have greatly improved my Bodies condition with my RA, without any testing! The doctors have ignored cannabis, until we user's dragged them to the water and made them drink! I love that some are interested and getting involved now, researching and testing is what they are good at, when you can open their minds to explore without preconceived notions blocking progress! When millions of persons are happy, healthier and becoming so,from a garden herb, it no longer can be denied that it is beneficial!

 

[Preston9mm]

You hit the nail on the head in regards to testing, versus home remedy! I wish I could have all my meds tested, however I have greatly improved my Bodies condition with my RA, without any testing! The doctors have ignored cannabis, until we user's dragged them to the water and made them drink! I love that some are interested and getting involved now, researching and testing is what they are good at, when you can open their minds to explore without preconceived notions blocking progress! When millions of persons are happy, healthier and becoming so,from a garden herb, it no longer can be denied that it is beneficial!

What always bugs me, are the doctors who are anti-cannabis, because it isn't "tested" but will quickly test 15 medications on ya to try finding one that works.
Even on my worst "whoops, these brownies are too strong" moment, I didnt have the side-effects of those prescriptions. Uhhh.... I'll stick to my "untested" bud. Thanks. LoL
-P

 

[Amy Gardner]

Even on my worst "whoops, these brownies are too strong" moment, I didnt have the side-effects of those prescriptions. Uhhh.... I'll stick to my "untested" bud. Thanks. LoL
-P

I’m about to do my first attempt at an acid cannabinoid infusion, to blend with the decarb’d infused oil I have already to (hopefully) get some acid cannabinoids in there . That video you shared back there Sue has a good reference to some great help for doing this (making acid form infusions).

 

[InTheShed]

I completely understand the desire for testing as it relates to cannabis as medicine. To me, testing is the key to repeatability, which is something I would think you would want for something you are using to treat a medical condition, particularly one with a window of survivability (like cancer) vs something you can work at over time (like RA or OA). I'm making capsules for my dad with dementia, and I use my Blueberry Auto bud for him and blend it with CBD oil. When I run out of that I will have to start over trying to find something with a similar cannabinoid/THC profile, and without testing I will be guessing at dosing as I did when I started. With access to testing I could know which of the available strains is closest and plug that in.

And I will only buy CBD oil with the mg/ml listed on the bottle, otherwise I would be blending blind with every new bottle I buy. Testing provides reliability, something anyone who practices any medicine (western or otherwise) relies on.

 

[SweetSue]

I completely understand the desire for testing as it relates to cannabis as medicine. To me, testing is the key to repeatability, which is something I would think you would want for something you are using to treat a medical condition, particularly one with a window of survivability (like cancer) vs something you can work at over time (like RA or OA). I'm making capsules for my dad with dementia, and I use my Blueberry Auto bud for him and blend it with CBD oil. When I run out of that I will have to start over trying to find something with a similar cannabinoid/THC profile, and without testing I will be guessing at dosing as I did when I started. With access to testing I could know which of the available strains is closest and plug that in.

And I will only buy CBD oil with the mg/ml listed on the bottle, otherwise I would be blending blind with every new bottle I buy. Testing provides reliability, something anyone who practices any medicine (western or otherwise) relies on.

I agree that affordable and reliable testing is the optimal reality, and the one I anticipate will become the norm. Something for easy home testing would be marvelous for those times when it’s enough to be in the ballpark, which, IMO, is where we are with cannabis most of the time.

When you’re working with patients, as in your case, where the cannabinoid counts really make a difference in the patient’s quality of life those testing options become even more desirable.

But even in the case of cancer I suspect we have a lot more wiggle room than we believe we do, and the chances of harming the patient are marginal, if at all, when the regimen is developed with at least a minimal amount of attention paid to ratios and terpenes.

Repeatability of a precise dose with a plant like cannabis can be tricky when the chemovars express so uniquely harvest to harvest. Testing would be required for such a goal to be attained, particularly if you were trying to keep terpenes under control as well.

I guess what I’m saying is I’d like testing to be available and affordable for everybody. I also believe cannabis can be consistently dispensed as a medicine without testing. This is presuming you have a clean crop to work with and practice cleanliness in production to minimze pollutants.

I tend to think of cannabis more and more as a food.

It frightens me a little to think of what’s being sold out there as CBD oil at inflated prices.

 

[SweetSue]

I swear.... the man’s gonna push me to learn to mind map. When I get to NOLA I’ll start with this one and map it out as best I can.

The supporting cellular biology information will make my brain explode. Lol!

This is part one of a 3-part series. It seemed like a smart thing to start at the beginning. I’ve read it through the first time, and OMG....it needs a few more times through and the development of some supporting information.

I really, really want to understand this enough to make it easier to grab.

ProfofPot

Endocannabinoid Receptors – More Than Just CB1 and CB2

• Pharmacology
• May 14, 2017
• Prof of Pot

You’ve heard of the two cannabinoid receptors, CB1 and CB2. Actually, endocannabinoids can bind to at least 8 more receptors.

The simple view of the endocannabinoid system is that there are two receptors, CB1 and CB2. Some may mention rumors of a third.
This view of the endocannabinoid system is outdated in many ways. I consider it to be incomplete now that our knowledge has advanced so much.
If only interested in the psychoactive effects of cannabis, then you probably don’t need to go beyond the CB1 receptor. However, if you are interested in the health effects of cannabis, then there is much more to understand.
NOTE: This is a 3 part series (you are in Part I):

• Part I: Endocannabinoid Receptors – More Than Just CB1 and CB2
• Part II: Receptor Dimerization – Expanding the Reach of Cannabinoids
• Part III: THC & CBD – Promiscuous Partners with Many Receptors

In the dark ages of the mid-1980’s, many thought that THC worked by perturbing cell membranes. This was proved wrong in 1988, when we saw that cannabinoids could bind to specific receptor sites in the rat brain. In 1990, the human CB1 receptor was identified as the primary receptor that mediated the effects of THC.

Of course, you wouldn’t have this receptor if no endogenous ligand exists. Anandamide (AEA) was the first endocannabinoid discovered to activate the CB1 receptor. Unlike many other signaling molecules that are produced ahead of time and stored in vesicles waiting to be released, anandamide was a lipid molecule produced on demand by a set of enzymes

This groundbreaking research was quickly followed by the discoveries of a second cannabinoid receptor, mostly expressed in immune cells, and a second endocannabinoid,2-arachidonylglycerol (2-AG).

Undoubtedly, this decade of the mid-80’s to mid-90’s will remain one of the most important in the history of cannabinoid research. However, research from much of the following decade is largely ignored by most cannabis sites.

There were important insights gained from the mid-90’s to mid-00’s that you rarely ever hear about. For example, the list of endocannabinoids has grown to include noladin ether, palmitoylethanolamine (PEA), virodhamine and oleoylethanolamide (OEA).

More importantly, research on endocannabinoid receptors has expanded. We now know that many effects of endocannabinoids are not mediated through either the CB1 or CB2 receptor. These include health-related effects on blood pressure, inflammation, pain, and cancer cell growth. In fact, endocannabinoids can directly bind to at least eight different receptors beyond CB1 and CB2.

Below, I will give an overview of the different receptors that are either part of the endocannabinoid system, or are part of a different signaling system, yet are still modulated by endocannabinoids.

Cannabinoid CB1 Receptor
The CB1 receptor is hands down the most famous of the endocannabinoid system. This receptor, like the next 4 that I describe, are part of a class of receptors called G protein-coupled receptors (GPCRs). These receptors sit within the cell membrane and upon activation, start a signaling cascade within the cell that leads to specific effects. The two most common endocannabinoids to activate CB1 are anandamide and 2-AG.

The highest levels of CB1 expression are in the central nervous system (CNS). In fact, there are more CB1 receptors in the brain than any other type of GPCR. However, despite descriptions as the “brain receptor” it is also found throughout the body in many different tissues: cardiovascular, reproductive, immune, gastrointestinal, and peripheral nerves to name a few important ones.

In 1999, the first mouse with a genetically-deleted CB1 receptor (i.e. a “CB1 knockout”) was reported. An excellent book chapter has reviewed the many functions of the CB1 receptor discovered through this approach.

Given the wide distribution of the CB1 receptor, it is not surprising that it seems to be involved in, well, just about everything. I can only give a high level summary, as any one of these points could be an entire article in itself.

• Regulates learning and memory
• Neuronal development & synaptic plasticity
• Regulates reward and addiction
• Reduces pain
• Reduces neuroinflammation and degeneration
• Regulates metabolism & food intake
• Regulates bone mass
• Cardiovascular effects

Cannabinoid CB2 Receptor
The CB2 receptor is located primarily in the periphery instead of the CNS. It is mainly expressed in immune cells, giving it an important role in inflammation. However, we now know that CB2 is expressed in a variety of cells, including those in the CNS, liver, and bone. CB1 is no longer considered to be the only cannabinoid receptor that affects memory and cognition.

The amino acid sequence of the CB2 receptor is relatively similar to the CB1 receptor. So not surprisingly, the CB2 receptor is activated by similar cannabinoids as the CB1 receptor, including anandamide and 2-AG.

Using mice with the genetically-deleted receptor, many functions of CB2 have been elucidated. Mice lacking CB2 had had more severe conditions in a variety of disease models:

• Allergic and autoimmune inflammatory diseases
• Osteoporosis (loss of bone mass)
• Neurodegenerative diseases
• Ischemic injury from stroke or heart attack
• Chronic pain
• Hepatic (liver) injury and disease
• Alcohol and nicotine addiction
• Weight gain
• Stress responses

Based on this animal data, there is no guarantee that activation of CB2 receptors will help these conditions in humans. For many of these conditions, there is additional supportive nonclinical and clinical evidence, but that is out of the scope of this article.


“Atypical” Cannabinoid Receptors
In most articles on the endocannabinoid system, the story stops there. However, let’s get to the exciting new research from the last two decades that is rarely talked about!

We have known for some time that the CB1 and CB2 receptors do not mediate all the actions of cannabinoids. How could we know this? Mice with genetically-deleted CB1 and CB2 receptors were crossbred to create mice that had neither receptor. If no other receptors were activated by cannabinoids, then there should be no effect of THC or anandamide in these mice.

However, starting with the first report in 1999, we have observed many different effects of cannabinoids in these double knockout mice. For example, cannabinoids were still able to affect blood pressure, pain, inflammation, and gastric motility in the absence of CB1 and CB2 receptors.

At this point, the hunt was on to find new cannabinoid receptors! Since then, we have discovered that endocannabinoids bind to many receptors that were not considered part of the endocannabinoid system.

GPR18
This receptor was discovered in 1997, but for several years it was an “orphan receptor”, meaning that they did not know what its ligand was. In 2006, a surprising discovery was made – this receptor could be activated by endocannabinoids!

GPR18 can be activated by anandamide, but it’s main endocannabinoid ligand appears to be N-arachidonyl glycine (NAGly), which is a metabolite of anandamide.

The GPR18 receptor is expressed highly in the spinal cord, small intestine, immune cells, spleen, bone marrow, thymus, lungs, testis and cerebellum.

GPR18 activation can lower blood pressure. It also has significant functions in immune cells. It acts as a powerful chemoattractant – meaning it induces migration of immune cells.

GPR55
This receptor has a similar story to GPR18. It was an orphan receptor for many years until its ligands were discovered. GPR55 is activated by the endocannabinoids 2-AG and anandamide, but its main ligand appears to be another putative endocannabinoid called lysophosphatidylinositol (LPI).

This receptor is expressed at high levels in the central nervous system, as well as adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder and kidneys. It’s wide tissue distribution gives it roles in a variety of body systems.

GPR55 activation causes hypotension (lowers blood pressure), is anti-inflammatory, and is in some cases anti-nociceptive (pain blocking). GPR55 regulates energy intake and expenditure, which could impact diseases such as obesity and diabetes. It is also expressed in bone cells with a possible role in osteoporosis. GPR55 is neuroprotective and decreased neurodegeneration in models of multiple sclerosis

GPR119
GPR119 expression is restricted to a limited number of tissues. It is primarily found in the pancreas and gastrointestinal tract – hinting that its role is the regulation of energy and metabolism.

GPR119 is activated primarily by the endocannabinoid OEA, with minimal activation by other endocannabinoids such as anandamide and 2-AG.

Activation reduces food intake, improves handling of blood sugar, and decreases body weight. These effects appear to be mediated through regulation of hormones such as insulin and GLP-1.

Vanilloid Receptors
Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed both on sensory neurons and in the brain. In sensory nerves, TRPV1 acts a sensor for things that could potentially cause tissue damage. It is activated in response to heat and proinflammatory substances, sending a pain signal to the brain. The most famous activator of TRPV1 is capsaicin, the ingredient found in chili peppers that causes a burning pain. Dysregulation of TRPV1 is also involved in chronic pain.

Interestingly, anandamide is an activator of the TRPV1 channel. Sensory neurons often co-express both the CB1 receptor and the TRPV1 receptor, making the role of anandamide in generating pain signals unclear.

TRPV1 plays a very different role in the brain, where its activation by anandamide seems to reduce pain.

Serotonin Receptors
There are many different serotonin (5-HT) receptor subtypes that mediate the different effects of serotonin. The 5-HT3 subtype is unique among the 5-HT receptors since it is a ligand-gated ion channel instead of a GPCR.

The 5-HT3 receptor is most well-known for mediated nausea and vomiting, particularly after chemotherapy. Several anti-nausea drugs work by inhibiting this ion channel. It also has a role in neuropathic pain.

Anandamide can directly bind to the 5-HT3 receptor and inhibit its activation. However, it doesn’t work by blocking the main serotonin binding site on the receptor. Instead, it binds to a different site and acts as a negative allosteric modulator. In other words, it changes the conformation of the receptor to minimize activation by 5-HT.

This inhibition of 5-HT3 is at least partly responsible for the analgesic effects of cannabinoids that are not mediated through the traditional CB1 or CB2 receptors.

Glycine Receptors
Glycine receptors (GlyRs) are ligand-gated ion channels which inhibit nerve activation. GlyRs are expressed in spinal interneurons, where they regulate pain transmission to the brain.

Anandamide is capable of directly binding to GlyRs and increasing channel activation. Anandamide does not bind the main agonist site nor can it activate GlyRs by itself. Like with 5-HT3 receptors, anandamide acts as an allosteric modulator. It binds a different site on the GlyR and enhances activation by glycine

This is another mechanism, independent of the CB1 and CB2 receptors, that endocannabinoids may reduce pain by acting at the spinal level.

Peroxisome Proliferator-Activated Receptors
Peroxisome proliferator-activated receptors (PPARs) are fundamentally different than the receptors described above. Rather than sit within the cell membrane, PPARs reside within the cell and can directly bind to DNA sequences and change transcription of targeted genes. There are three isoforms of PPAR: α, β, and γ.

Anandamide and 2-AG are potentially able to activate PPARα, but activation is much stronger by the endocannabinoids OEA and PEA. Anandamide and 2-AG may also be able to activate PPARγ.

PPARs regulate cellular functions in almost every tissue. Some of the effects of endocannabinoids which may be at least partially attributed to either PPARα or PPARγ activation include neuroprotection against ischemia and neurodegeneration, reduced nicotine addiction, analgesia, anti-tumor effects, vasorelaxation, weight reduction, and reduced inflammation.

Interestingly, there are already approved drugs which act through PPARα activation (for treatment of cholesterol disorders and triglyceride metabolism) and through PPARγ activation (for tratment of insulin resistance and to decrease blood glucose levels.)

Other Possible Endocannabinoid Targets
Other potential targets for endocannabinoids have been identified. However, it is not clear if these play a significant role in the effects of endocannabinoids. These include voltage-gated ion channels, NMDA receptors, acetylcholine receptors, and glycine transporters.

 

[Derbybud]

WOW my head hurts

 

[InTheShed]

There's a cannabinoid receptor for that!

 

[Derbybud]

I better start growing a tent full of that.

 

[SweetSue]

There's a cannabinoid receptor for that!

 

[Preston9mm]

There's a cannabinoid receptor for that!

Zing!

 

[SweetSue]

Abbreviations
2-AG: 2-Arachidonoylglycerol

AEA: Anandamide

bp: Base pairs - a unit consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix, and contribute to the folded structure of both DNA and RNA.

CNS: Central nervous system

DAGL: Diacylglycerol lipase The diacylglycerol lipases (DAGLs) hydrolyse diacylglycerol to generate 2-arachidonoylglycerol (2-AG), the most abundant ligand for the CB1 and CB2cannabinoid receptors in the body. DAGL-dependent endocannabinoid signalling regulates axonal growth and guidance during development, and is required for the generation and migration of new neurons in the adult brain. At developed synapses, 2-AG released from postsynaptic terminals acts back on presynaptic CB1 receptors to inhibit the secretion of both excitatory and inhibitory neurotransmitters, with this DAGL-dependent synaptic plasticity operating throughout the nervous system. (Abstract)



DSE: Depolarization-induced suppression of excitation

DSI: Depolarization-induced suppression of inhibition

Prefrontal Cortex Stimulation Induces 2-Arachidonoyl-Glycerol-Mediated Suppression of Excitation in Dopamine Neurons
Miriam Melis, Simona Perra, Anna Lisa Muntoni, Giuliano Pillolla, Beat Lutz, Giovanni Marsicano, Vincenzo Di Marzo, Gian Luigi Gessa and Marco Pistis
Journal of Neuroscience 24 November 2004, 24 (47) 10707-10715; DOI: Prefrontal Cortex Stimulation Induces 2-Arachidonoyl-Glycerol-Mediated Suppression of Excitation in Dopamine Neurons

• Article
• Figures & Data
• Info & Metrics
• eLetters
• PDF

Abstract
Endocannabinoids form a novel class of retrograde messengers that modulate short- and long-term synaptic plasticity. Depolarization-induced suppression of excitation (DSE) and inhibition (DSI) are the best characterized transient forms of endocannabinoid-mediated synaptic modulation. Stimulation protocols consisting of long-lasting voltage steps to the postsynaptic cell are routinely used to evoke DSE-DSI. Little is known, however, about more physiological conditions under which these molecules are released in vitro. Moreover, the occurrence in vivo of such forms of endocannabinoid-mediated modulation is still controversial. Here we show that physiologically relevant patterns of synaptic activity induce a transient suppression of excitatory transmission onto dopamine neurons in vitro. Accordingly, in vivo endocannabinoids depress the increase in firing and bursting activity evoked in dopamine neurons by prefrontal cortex stimulation. This phenomenon is selectively mediated by the endocannabinoid 2-arachidonoyl-glycerol (2-AG), which activates presynaptic cannabinoid type 1 receptors. 2-AG synthesis involves activation of metabotropic glutamate receptors and Ca2+mobilization from intracellular stores. These findings indicate that dopamine neurons release 2-AG to shape afferent activity and ultimately their own firing pattern. This novel endocannabinoid-mediated self-regulatory role of dopamine neurons may bear relevance in the pathogenesis of neuropsychiatric disorders such as schizophrenia and addiction.

• CB1
• dopamine
• endocannabinoid
• excitatory transmission
• midbrain
• retrograde signal

View Full Text

Whether it's my slow-ass iPad or this platform, I've reached my limit for the night. When I throw the iPad across the floor in frustration because I can't get a simple thing to copy and paste without three tries it's time to walk away.


ES cells: Embryonic stem cells

FAAH: Fatty acid amide hydrolase

frt: FLP recombinase recognition target

GDE1: Glycerophosphodiester phosphodiesterase 1

LTP: Long-term potentiationm

PFC: Medial prefrontal cortex

mRNA: Messenger RNA

NAE: N-Acylethanolamine

NAPE-PLD: N-Acyl phosphatidylethanolamine phospholipase D

NAPEs: N-Acyl phosphatidylethanolamines

neo: Geneticin-resistance gene (aminoglycoside phosphotransferase)

NKT cell: Natural killer T cell

PGK: Phosphoglycerokinase

RNA: Ribonucleic acid

siRNA: Small interfering RNA

THC: Tetrahydrocannabinolt

TA: Tetracycline-dependent transcriptional activator

 

[SweetSue]

The EssentiaList
Bigfork’s Essential Stuff Blog — Bringing People Together
« Fats for Soapmaking
Gathering Summary: Smart Use of Trees by Sally Janover, October 27, 2010 »
Basic Metabolism of Fats
by Catherine Haug, December 17, 2010
NOTE: This overview is another post in the Cat’s Fat’s series.

Synopsis:

Metabolism is the process used by the body to keep it functioning, and fats are an essential part of this function.

In addition to being a part of our diet, many fats can be made from carbohydrates or proteins in the liver. However, the essential fats (Omega-3 and Omega-6) cannot be made in our liver and must be obtained in our diet.

The process of digestion, absorption & metabolism of fats is not the same for all types of fatty acids. And while all fats can be used for energy production (just as carbs and proteins) they are also used for other purposes.

Excess fats are stored primarily in adipose tissue (fat cells), but may also be stored in the liver, for future use. Furthermore, excess dietary carbohydrates are converted to fats.

This article addresses:

• Short-chain (SCFA) and medium-chain (MCFA) fatty acids
• Long-chain fatty acids (LFCA)
• Fats and energy production
• Conversion of carbs to body fat

See also The Medical Biochemistry Page on Carbohydrate Metabolism (5) and Fat Metabolism(6) for much more detail.

Short- & medium-chain fatty acids
Short- & medium-chain fatty acids (SCFAs & MCFAs) are all saturated, and are slightly polar (slightly charged) so can form a suspension in watery fluids. An abundance of SCFAs in the bowel has been associated with reduced risk of (4):

• irritable bowel syndrome;
• inflammatory bowel disease,
• cardiovascular disease, and
• cancer.

NOTE: SCFTs are also produced in the bowel by probiotic digestion of dietary fiber. These fatty acids are then metabolized in the same manner as dietary SCFTs.
Contrary to popular belief concerning all saturated fats, recent research has shown that MCFAs affect control over adipose (fat) tissue to reduce fat mass, body weight and particularly body fat. (1)

Digestion & absorption of SCFAs & MCFAs

The first step in digesting fats is to strip (hydrolyze) the individual fatty acids from the glycerol backbone, in an enzyme-driven process called ‘lipolysis.’ For short- and medium-chain fatty acids, the presence of bile is not required.

Once lipolysis is complete, these relatively small and slightly polar molecules are readily absorbed through the intestinal wall into the hepatic portal vein for transport to the liver, where they are a preferred source of energy. This is a passive process, meaning that they do not require the assistance of proteins and cholesterol for transport across the intestinal wall.

Metabolism of SCFAs & MCFAs

If SCFAs and MCFAs are not being used for energy production in the liver, they can be actively transported from the liver to muscle and other cells for energy production within the mitochondria.(3) This transport involves bundling with longer chain fatty acids, cholesterol and protein as triglyceride particles (TGs), LDL or HDL cholesterol for transport in the blood.

Long chain fatty acids

Long-chain fatty acids (LCFAs) can be saturated, mono-unsaturated or poly-unsaturated, and comprised of 14 or more carbons in the chain. They can also be branched-chain.

Digestion & absorption of LCFAs

All long chain fatty acids require bile salts from the liver for lipolysis, which is the first step of their digestion.

Once freed from the glycerol backbone, they are too large to move through the intestinal wall on their own. Instead, they must first be coupled with special proteins and cholesterol as chylomicrons (a type of cholesterol particle) for active transport through the intestinal wall, then carried to all the cells of the body for metabolic use.

Metabolism of LCFAs

While LCFTs can be used for energy production in cells, they are also an integral part of cell and mitochondrial membranes, where there is a high demand for them. Fatty acids in the membrane are in constant state of flux, so that a steady supply of replacements is always needed. Saturated LCFAs provide stability for the membrane; unsaturated LCFAs provide flexibility. And all types are involved in communication between the inside of the cell and the cell’s surroundings.

Poly-unsaturated LCFAs in cell membranes are used to produce prostaglandins, which are localized hormones that affect the immediate surroundings of the cell or the cell itself, in response to stress triggers such as: trauma, virus, bacteria, heavy metals, free-radical or glycation products and other toxins. In this role, LCFAs are an important part of our immune system.

Generally, prostaglandins made from omega-3 fatty acids fight inflammation, while those made from omega-6 fatty acids promote inflammation; but there are exceptions to this generalization. Both inflammatory and anti-inflammatory processes are important for healing.

It is important to note that man-made poly-unsaturated fats, such as those made by partial hydrogenation of vegetable oils to make margarine or shortening, cannot form prostaglandins and are always pro-inflammatory.

Fats and energy production

As mentioned above, fats can be used for energy production in the cells.

• SCFAs and MCFAs produce energy in the liver, to support it’s detox function.
• LCFAs are transported in the blood to cells in other parts of the body (primarily muscles) for energy production via the TCA cycle (Tricarboxylic Acid cycle). This is an enzyme driven process that produces energy in the form of ATP (Adenosine Triphosphate), and used by the cell to keep it alive and doing what it is supposed to do.

For some people, fats are a preferred source of muscle energy; for others, carbs are the preferred source. This preference depends upon whether the parasympathetic (7) or Sympathetic (7) nervous system is dominant.

Fats can also be used by cells for cell and mitochondrial membranes, and production of prostaglandins (a type of hormone). Or for insulation of nerve tissue.

Conversion of Carbs to Body Fat

Body fat

Contrary to general belief, dietary fats are not the major contributor to body fat. Rather it is excess dietary carbohydrates that are the primary cause of belly fat accumulation. Excess dietary fats are far more likely to be used for other purposes, such as incorporation into cell membranes, or to form insulation for nervous tissue.

Review of carbohydrates

• Simple Sugars: The primary carb metabolized in the body to produce energy, such as for muscle or brain activity, is glucose, a simple sugar (mono-saccharide). Fructose is another simple sugar, but is metabolized only in the liver. Other simple sugars can also be metabolized, but are not discussed here.
• Di-saccharides must first be broken down into their constituent simple sugars before they can be metabolized; for example, sucrose(table sugar) is broken down into one molecule of glucose and fructose.
• Starches are broken down by digestive enzymes into individual molecules of glucose.
• Fibers: We don’t have the enzymes to break down fibers so they do not produce simple sugars. Instead they are either excreted, or converted to short chain fatty acids (acetic, propionic, lactic, malic, and glucuronic) in the gut by the action of beneficial bacteria (probiotics), then carried to the liver where they are the primary source of energy for detox functions.

See Medical Biochemistry Page on Carbohydrate Metabolism and Non-glucose Sugar Metabolism, for more. (5)

Metabolism of glucose

Glucose is readily absorbed through the intestinal wall into the blood, and then carried to the cells of the body, primarily muscle and brain cells, where it is burned for energy.

But before it can be burned, it must be taken up by the cell, a process that requires insulin, insulin receptors, and active-transport molecules, because the cell membrane is not friendly to glucose on its own. Once in the cell, glucose enters the glycolytic pathway and TCA cycle (Tricarboxylic Acid cycle), enzyme processes that produce energy in the form of ATP (Adenosine Triphosphate).

If the cells already have enough ATP, glucose is converted into glycogen (a type of starch) for temporary storage in the cell. The glycogen can be converted back to glucose, when more energy is needed.

However, when the cells have enough glucose/glycogen, the insulin receptors on the cell membrane are turned off, so that no more glucose can be taken into the cell. This results in a buildup of glucose in the blood, which must be dealt with to avoid catastrophic problems such as coma.

Storage of excess blood sugar

Excess glucose in the blood is taken to the liver where it may be converted to glycogen for temporary storage. However, if the liver has enough glycogen, the glucose is converted into saturated fatty acids which are incorporated into triglycerides (fat). These are then transported by cholesterol particles (LDL and TGs) to the fat cells of the body, primarily those in the belly.

Metabolism of Fructose

Fructose metabolism is distinctly different from that of glucose. It does not invoke the insulin response but rather is taken directly to the liver after absorption from the gut. In the liver it is converted into glucose. (5)

While the glucose can be burned in the liver for energy, the liver prefers to burn short chain fatty acids. Instead, it is either:

• Converted into glycogen for storage in the liver cells; or
• Into saturated fatty acids, which are incorporated into triglycerides (fat), then transported via cholesterol particles (LDL and TGs) to fat cells, primarily in the belly. (5)

The latter happens when the liver has enough stored glycogen from excess glucose as well as fructose.
Modern diets are much higher in fructose than traditional diets because of the use of high fructose corn syrup and agave nectar in our foods. These are a leading cause of belly fat and obesity.

Sources

1. Medium-Chain Triglycerides; a Review: www.sciencedirect.com
2. What is Life: Fatty Acids, an overview: www.whatislife.com/reader2/Metabolism/pathway/fattyacids.html
3. PubMed, Medium chain fatty acid metabolism and energy expenditure: obesity treatment implications: www.ncbi.nlm.nih.gov/pubmed/9570335
4. Topical Review: Short Chain Fatty Acids and Colonic Health, by E. Hijova & A. Chmelarova: www.bmj.sk/2007/10808-06.pdf
5. The Medical Biochemistry Page: on Carbohydrate Metabolism: themedicalbiochemistrypage.org/glycolysis.html and on Non-Glucose Sugar Metabolism: themedicalbiochemistrypage.org/non-glucose-sugar-metabolism.html
6. The Medical Biochemistry Page: on Fat & Lipid Metabolism: themedicalbiochemistrypage.org/lipid-synthesis.html
7. Wikipedia on Sympathetic & Parasympathetic nervous systems: en.wikipedia.org/wiki/Autonomic_nervous_system

This entry was posted on Monday, January 10th, 2011 at 7:20 pm and is filed under Cat's Fats, Food-Nutrition-Health. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed.
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