How we get a fatty liver. An attempt at a simple explanation for a complex process

[carolT]

This study describes the differences between two pathways that can lead to NAFDL. The one called Primary (PRIM) begins with increased de novo lipogenesis (DNL) in the liver. The Secondary pathway (SEC) is a result of an increased free fatty acid FFA load on the liver coming from impaired adipose tissue storage.

First, these two routes have a common denominator; they both involve an adequacy of choline supply to export fats from the liver. That’s the part at the top involving alternate forms of SREBP-1c. SREBPs regulate the synthesis of phosphatidylcholine at several levels. Triglycerides created in the liver must be exported as VLDL. Masterjohn has written extensively about choline deficiency and fatty liver here:
https://chrismasterjohnphd.com/blog/2016/04/24/start-here-for-fatty-liver-disease/
There are also some genetic indicators of impaired choline sysnthesis here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574369/

Now to the study at hand.
The PRIM pathway involves hepatic DNL. Creating fattty acids from fructose or alcohol substrates falls into this category.

Liver-specific overexpression of SREBP-1c and increased hepatic DNL in the PRIM mouse model leads to accumulation of DAGs and triacylglycerols (TAG) and development of NAFLD. NAFLD in PRIM associates with decreased insulin signaling and higher hepatic glucose output.
…ChREBP-mediated lipogenesis in adipose tissue and fat mass are increased, which could protect from hyperglycemia and peripheral IR.

Note this last part. Increased storage of fat in adipose tissue is protective against fatty liver accumulation in this model.

The SEC pathway does not involve an increase liver DNL, and is a function of adipose health. Overloaded adipose tissue releases FFA when insulin signaling can no longer keep fat in the fat cells. This occurs when a person’s adipose capacity is exceeded, regardless of weight. Healthy fat cells = properly stored fat and systemic insulin sensitivity. Unhealthy fat cells = runaway lipolysis and excess FFA delivered to the liver.

On the other hand, SEC mice are characterized by loss of adipose tissue and ectopic lipid accumulation in both liver and skeletal muscle… Liver and skeletal muscle are both characterized by decreased insulin sensitivity.
Moreover, accumulation of extrahepatic lipids in SEC but not intrahepatic lipids in PRIM associates with portal and lobular inflammation of the liver.

So, does fructose cause fatty liver? It depends.
In the PRIM model it would take an approprite level of fructose to overcome a lack of available choline, thereby trapping fat in the liver instead of exporting it to adipose tissue. BUT fructose also increases the insulin response to glucose and this will exacerbate the SEC pathway to fatty liver, in which liver disease is downstream of the effects of glucose and insulin.

The next post on this topic will involve inflammation and immune system responses and the role they play in insulin resistance… someday

[echo2080]

I have read the conclusion of the study again and again but found that I couldn’t really understand its conclusion due to my poor English reading skills, could anyone kindly interpret the conclusion in the study below? Many thanks!

In conclusion, hepatic insulin resistance originates from lipotoxicity but not from lower mitochondrial capacity, which can even transiently adapt to increased peripheral lipolysis. Peripheral insulin resistance is prevented during increased hepatic lipogenesis only if adipose tissue lipid storage capacity is preserved.

[ctviggen]

I’m not sure your English reading skills are poor. As a born-in-the US person with an engineering and law degree, I don’t know what that says.

I think I’d have to read the study and quite a few more to understand that.

[Pjam]

Agreed. Echo your English is excellent. It’s the science that’s hard. You’d need to study not English but Anatomy, chemistry, Biology and probably more !!

[cvkemp]

As one of my doctors told me so many years ago when I had first lost about 90 pounds. Eat real food, stay away from highly refined and processed foods, stay away from fast food, and stay away from soft drinks and fruit juices. But to eat a diet rich in protein, good fat and plenty leafy veggies, and moderate amount of fruit. she also said nuts if I wasn’t allergic to them. She stressed real food, she also stressed stay away from refined and processed foods. She called out cereals, and most bread and bread products. This was back in 2011 or early 2012, back during the time that everyone else was preaching the DASH Diet for blood pressure issues like I have had. She was ahead of her time it seems. I followed her advice until I got lost in the stress of forced retirement, and moving. I just pulled out my journal notes from my visits to that wonderful caring doctor that was a drug company and insurance company be damned type of person.

[PaulL]

In conclusion, hepatic insulin resistance originates from lipotoxicity but not from lower mitochondrial capacity, which can even transiently adapt to increased peripheral lipolysis. Peripheral insulin resistance is prevented during increased hepatic lipogenesis only if adipose tissue lipid storage capacity is preserved.

It means that the insulin resistance in the liver originates in eating liver toxins (alcohol, fructose, and branched-chain amino acids, say; since the pathway that handles them is easily overwhelmed). The problem does not come from a reduction in the liver cells’ ability to metabolise fat. And the only way to prevent insulin resistance of the liver when the liver is making too much fat is to make sure the fat cells (adipocytes, adipose tissue) have room to store fat. (That should be easy, right? )

The easier way is to eliminate sugar from the diet altogether, to greatly reduce alcohol consumption, and to eat foods low in branched-chain amino acids. The BCAA’s are essential amino acids, but we don’t need very much of them. The sugar is important to cut out because it’s a disachharide (a glucose molecule bonded to a fructose molecule), and it’s the fructose moiety that damages the liver. Alcohol is metabolised by the same liver pathway, and again, too much of it causes fatty liver disease. And BCAA’s are also handled by the same pathway. So reversing fatty liver disease requires reducing the total burden on that liver pathway. Then the fat cells can do whatever they want.

[echo2080]

As a born-in-the US person with an engineering and law degree, I don’t know what that says.

, I feel better when I see this! Haha…

And the only way to prevent insulin resistance of the liver when the liver is making too much fat is to make sure the fat cells (adipocytes, adipose tissue) have room to store fat

Thanks PauIL, I think I got it!

[scaperdude]

It means that the insulin resistance in the liver originates in eating liver toxins (alcohol, fructose, and branched-chain amino acids, say; since the pathway that handles them is easily overwhelmed).

Yep. In the SAD about 60% of the calories eaten are processed foods. These are the foods that get loaded up with fructose from sugar and high fructose corn syrup mostly. The vast majority of the problem is the fructose from these and other sources. The liver just has nothing to do with the huge amount it keeps getting except turn it into fat - hence the fatty liver disease.

The easier way is to eliminate sugar from the diet altogether, to greatly reduce alcohol consumption, and to eat foods low in branched-chain amino acids. The BCAA’s are essential amino acids, but we don’t need very much of them.

The BCAAs are the amino acids we need the most to make and maintain muscle. I even add them to my protein powders, because the base is plant proteins which are generally somewhat low in these amino acids compared to our muscle needs. For example the BCAAs are going to be the highest consumed in a carnivor diet. I don’t consider them to be a problem - at least not compared to fructose. In reality fructose is by far the main driver of fatty liver disease in the SAD.

[Pjam]

The BCAAs are the amino acids we need the most to make and maintain muscle

OK, I’ve had to search BCAA’s. Obviously too clever for me but as an active person with a liver I might benefit, and it appears they wouldn’t do any harm if unrequired?

[ctviggen]

BCAAs are strange. I just saw one study about metformin where metformin interfered with BCAAs in heart failure, and it was a good thing. There was also a liver aspect. I’ll see if I can find the study.

[ctviggen]

Here’s that metformin study:

Amino acid homeostasis is a target of metformin therapy

[PaulL]

The BCAAs are the amino acids we need the most to make and maintain muscle. I even add them to my protein powders, because the base is plant proteins which are generally somewhat low in these amino acids compared to our muscle needs. For example the BCAAs are going to be the highest consumed in a carnivor diet. I don’t consider them to be a problem - at least not compared to fructose. In reality fructose is by far the main driver of fatty liver disease in the SAD.

None of those three things (alcohol, fructose, and BCAA’s) is a problem for the liver, provided that the total consumption of them is at a rate the liver can handle. So if you are going to eat quantities of BCAA’s, then you want to cut back on alcohol and fructose. If you are going to eat quantities of fructose, you want to cut back on alcohol and BCAA’s. And so forth.

Exceeding that liver pathway is what causes de novo lipogenesis, which, if we don’t stop triggering it, leads to fatty liver, steatohepatitis, and eventually cirrhosis. This progression is well-known in the context of excessive alcohol consumption and is now being associated with excessive fructose consumption, either together with alcohol (as in the case of many adults) or alone (as in the case of children). Fortunately, fatty liver disease can be quickly reversed by stopping or greatly limiting the consumption of the substances that are handled by this pathway.

[PaulL]

OK, I’ve had to search BCAA’s. Obviously too clever for me but as an active person with a liver I might benefit, and it appears they wouldn’t do any harm if unrequired?

The branched-chain amino acids (leucine, iso-leucine, and valine) are among the 9 essential amino acids. However, while we require them in our diet, we don’t need much, under normal circumstances. Body builders who need BCAA’s to aid in muscle growth are the main people who need to worry about getting enough BCAA’s. And, as mentioned, there is a limit here, in that the liver pathway that handles BCAA’s is easily overwhelmed, so total alcohol, fructose, and BCAA consumption needs to be kept to a rate the liver can handle. My conclusion is that muscle building will therefore work best if we avoid alcohol and fructose, so as to be able to consume the maximum amount of BCAA’s the liver can handle.