Tale of Two Fatty Livers A paper published in @Cell_Metabolism...
Nick Norwitz MD PhD@nicknorwitz
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Jan 11, 2025
~3 min read
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Tale of Two Fatty Livers
A paper published in @Cell_Metabolism about Fatty Liver Disease was a thinker!
🌟If you can follow this Tweet or Video, Gold star!🌟
Video: youtu.be/atXz67L8Ckg
Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly common. Simply, it can be thought of as a function of more fat in the liver being produced, via “de novo lipogenesis’ (DNL) than is burned, through beta-oxidation of fatty acids and ketogenesis.
For our purposes, let’s say most cases of fatty liver can be reduced to that imbalance. For example, you eat a diet rich in high-fructose corn syrup, stimulating DNL and the build-up of fat in the liver and don’t give it a chance to get burned… NAFLD… sad
BUT, here’s where things get interesting…
A common genetic variant "patatin-like phospholipase domain containing 3" (PNPLA3) protein (variant I148M) is a major risk factor for NAFLD. For the rest of this Tweet, I’ll just call this “PNPLA3 mutant”, which has impaired function as compared to the normal PNPLA3. How PNPLA3 mutant contributes to NAFLD was the topic of this paper.
But here’s what’s odd: patients with PNPLA3 mutant have decreased DNL (1E) and increased ketogenesis (including post-prandial, 2B) and ketone levels (1G), which you would think would oppose the accumulation of liver fat, right? Basically, more fat out than in = less liver fat? So why, then, are patients with this mutation more likely to get NAFLD? Indeed, they do have more triglycerides in their livers (1D)
What gives?!
The answer lies in “mitochondrial dysfunction.” The researchers found that the PNPLA3 mutant patients had lower activity of a protein that generates a precursor of DNL (citrate). The result is that, relative to controls (“normies”) substrates get shuttled more to ketogenesis than DNL. You’d think this is a good thing, but here’s the catch: run an engine too hot, and it hurts the engine…
In PNPLA3 mutants, shuttling of fatty acids to beta oxidation and ketogenesis causes of reduction of NAD+ to NADH, increasing the NADH/NAD ratio or “redox state.” In my interpretation of the text, it appears this is what may be to blame. The researchers write:
“Hepatic mitochondrial redox state (i.e., [NADH]/[NAD+] ratio), was significantly higher in [PNPLA3 mutants] than non-carriers. This is consistent with hepatic mitochondrial reductive stress secondary to excessive b[eta]-oxidation of surplus fatty acids. We have recently demonstrated that increased hepatic mitochondrial redox state as determined by plasma b-hydroxybutyrate/acetoacetate ratio is associated with the severity of NAFLD.”
So, let’s summarize:
- PNPLA3 mutation is a major risk factor for NAFLD
- PNPLA3 mutants have lower DNL, higher ketogenesis, which you’d think would oppose NAFLD… but this might be a ‘chicken and the egg’ scenario
- PNPLA3 mutants preferentially shuttle substrates towards mitochondrial beta oxidation and ketogenesis, but in a manner that is ‘tuned up’ relative to physiological norm… leading to an increased “redox state” (NADH/NAD ratio) – or what one could call an ‘electron imbalance’ which creates a “stress” on hepatic mitochondria and – overtime - associates with the severity of NAFLD
FWIW, I think there are a lot of unanswered questions and loose ends on this one. I actually wanted to do this Tweet to consolidate my own thoughts, perhaps in the hopes that someone picks up on something essential that I overlooked. Or, maybe, we’re just at the boundaries of knowledge and will have to wait for the next paper.
In any case, I thought this was a good lesson in divergence from expectations and how, in biology, too much of a “good” thing, overtime, can have unintended consequences that we can’t always predict.
video: youtu.be/atXz67L8Ckg
paper: cell.com/cell-metabolis…
A paper published in @Cell_Metabolism about Fatty Liver Disease was a thinker!
🌟If you can follow this Tweet or Video, Gold star!🌟
Video: youtu.be/atXz67L8Ckg
Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly common. Simply, it can be thought of as a function of more fat in the liver being produced, via “de novo lipogenesis’ (DNL) than is burned, through beta-oxidation of fatty acids and ketogenesis.
For our purposes, let’s say most cases of fatty liver can be reduced to that imbalance. For example, you eat a diet rich in high-fructose corn syrup, stimulating DNL and the build-up of fat in the liver and don’t give it a chance to get burned… NAFLD… sad
BUT, here’s where things get interesting…
A common genetic variant "patatin-like phospholipase domain containing 3" (PNPLA3) protein (variant I148M) is a major risk factor for NAFLD. For the rest of this Tweet, I’ll just call this “PNPLA3 mutant”, which has impaired function as compared to the normal PNPLA3. How PNPLA3 mutant contributes to NAFLD was the topic of this paper.
But here’s what’s odd: patients with PNPLA3 mutant have decreased DNL (1E) and increased ketogenesis (including post-prandial, 2B) and ketone levels (1G), which you would think would oppose the accumulation of liver fat, right? Basically, more fat out than in = less liver fat? So why, then, are patients with this mutation more likely to get NAFLD? Indeed, they do have more triglycerides in their livers (1D)
What gives?!
The answer lies in “mitochondrial dysfunction.” The researchers found that the PNPLA3 mutant patients had lower activity of a protein that generates a precursor of DNL (citrate). The result is that, relative to controls (“normies”) substrates get shuttled more to ketogenesis than DNL. You’d think this is a good thing, but here’s the catch: run an engine too hot, and it hurts the engine…
In PNPLA3 mutants, shuttling of fatty acids to beta oxidation and ketogenesis causes of reduction of NAD+ to NADH, increasing the NADH/NAD ratio or “redox state.” In my interpretation of the text, it appears this is what may be to blame. The researchers write:
“Hepatic mitochondrial redox state (i.e., [NADH]/[NAD+] ratio), was significantly higher in [PNPLA3 mutants] than non-carriers. This is consistent with hepatic mitochondrial reductive stress secondary to excessive b[eta]-oxidation of surplus fatty acids. We have recently demonstrated that increased hepatic mitochondrial redox state as determined by plasma b-hydroxybutyrate/acetoacetate ratio is associated with the severity of NAFLD.”
So, let’s summarize:
- PNPLA3 mutation is a major risk factor for NAFLD
- PNPLA3 mutants have lower DNL, higher ketogenesis, which you’d think would oppose NAFLD… but this might be a ‘chicken and the egg’ scenario
- PNPLA3 mutants preferentially shuttle substrates towards mitochondrial beta oxidation and ketogenesis, but in a manner that is ‘tuned up’ relative to physiological norm… leading to an increased “redox state” (NADH/NAD ratio) – or what one could call an ‘electron imbalance’ which creates a “stress” on hepatic mitochondria and – overtime - associates with the severity of NAFLD
FWIW, I think there are a lot of unanswered questions and loose ends on this one. I actually wanted to do this Tweet to consolidate my own thoughts, perhaps in the hopes that someone picks up on something essential that I overlooked. Or, maybe, we’re just at the boundaries of knowledge and will have to wait for the next paper.
In any case, I thought this was a good lesson in divergence from expectations and how, in biology, too much of a “good” thing, overtime, can have unintended consequences that we can’t always predict.
video: youtu.be/atXz67L8Ckg
paper: cell.com/cell-metabolis…
