Fatty Liver Disease

Please note in readying this report on Cu(I)NA2  and fatty liver disease, the authors did not compare Cu(I)NA2  with another dietary copper supplement such as cupric (+2) citrate.  Therefore the conclusions are not unique to Cu(I)NA2. Do not take anything in this post as medical advice. Feel free to discuss this post with your physician.

This particular study came out of the Department of Physiology of Aswan University, in Aswan, Egypt [1].  The Liver Foundation estimates that approximately 30% of the U.S. population suffers from non alcoholic fatty liver disease and 5% are afflicted by  its subtype nonalcoholic steatohepatitis.  These numbers translate to about 100 million individuals in the United States living with  nonalcoholic fatty liver disease.  The global prevalence of fatty liver disease is  about as high.  Hegazy and coworkers were not interested in the mechanisms of moving fats out of the liver and into the blood stream.  They simply wanted to know if Cu(I)NA2 might relieve the inflammation associated with fatty liver disease.  Copper might have a role in both.

Fatty liver disease

Fatty liver disease is, very simply, the abnormal accumulation of fats in the liver.  Alcoholism is a main cause of fatty liver disease.  Non alcoholic fatty liver disease my be caused dietary deficiencies, metabolic abnormalities, drugs and toxins, and immune responses. These  authors chose to induce FLD in  rats with a methionine- and  choline deficient diet (MCDD).

What are methionine and choline?

Methionine is an essential amino acid that participates in many enzymatic reactions as a methyl donor.  DNA methylation is one of many of these reactions.  Note the methyl group in Figure 1c.  Choline (Fig 1c) is the basic constitute of lecithin (phosphatidyl choline), a phospholipid found in plant and animal cells.  Choline may also serve as a methyl donor.  Hydrogens in the structures in Figure 1c are “understood.”  The end of the sticks are understood to be methyl groups (-CH3).  Dietary deficiency choline may result in accumulation of fat in the liver due to lack of very low density lipoprotein (VLDL) needed to transport fats out of the liver.  Methionine deficiency may cause general liver damage that may be clinically measured by the release of the liver enzyme alanine amino transferase (ALT) into the blood.    PubChem tells us that choline may be used to synthesize betaine.

Choline deficiency in dairy cattle transitioning from being pregnant to being milk producers is an industry concern [2].  One of the industry challenges is protecting the dietary choline from the contents of the rumen.

Figure 1 The intersection of a methionine [1] and b choline pathways.  c a structure of methionine and chloine. d In addition to B12, methyl synthase has Mg2+ cofactors.

Why Copper?

A 1999 study examined the influence of copper deficiency in rats on folate and homocysteine synthesis.  Hepatic folate, and plasma vitamin B-12 concentrations were similar in both groups [3].  Homocysteine in the blood plasma increased, most likely the result of a decrease in hepatic methionine synthase (MS) activity [3].  The authors speculated that MS might be a cuproenzyme in addition to requiring B12 cofactor.  Twenty years later, we still have no clue.  Rat methionine synthase has three amino acids that interact with  Mg2+ and two that interact with K+ these were found by following the UniProt line to  an X-ray crystal structure of methionine synthase. [4]

Figure 2 Interaction of amino acids in methionine synthase with ATP and free methionine , adapted from [4]

One would think that if Cu2+  can substitute for Mg2+  in methionine synthase, we’d not know it by now.  Mg has only one oxidation state.   Cu has two.  The implications on the catalytic process would be interesting, if such a substitution were the case. The answer may lie in the affect of Cu on gene expression.

Cu(I)NA2 protects the fatty liver from further damage

Figure 3 from [1]  Effect of CNC, Cu(I)NA2, on liver enzyme activity in the serum of rats with fatty liver (mean±standard deviation, n=10).Means with different superscripts in the same row are significantly different at p<0.05. CNC=Copper-nicotinate complex, MCDD=Methionine- and choline-deficient diet, ALT=Alanine aminotransferase, AST=Aspartate aminotransferase, GGT=Gamma glutamyl transferase

Note that CNC,  Cu(I)NA2, brings the activities of liver in the serum down to control levels even in the presence of methionine and choline deficiency.

Figure 4 from [1]  Effect of CNC on oxidative/anti-oxidative markers in liver homogenate of rats with fatty liver (mean±standard deviation, n=10).  Means with different superscripts in the same row are significantly different at p<0.05. CNC=Copper-nicotinate complex, MCDD=Methionine- and choline-deficient diet

Note that Cu(I)NA2, brings reduced glutathione to control levels in the fatty liver model.    Malondialdehyde, a marker of reactive oxygen species degradation of polyunsaturated fatty acids,   is  decreased to control levels. Cu(I)NA2 almost doubles superoxide dismutase activity [1].  The authors did not distinguish between superoxide mimetic activity of  Cu(I)NA2  alone or in intracellular Cu/Zn SOD1 or extracellular Cu/Zn SOD3 [1].   These authors also looked at expression at various cytokines associated with inflammation.

Copper regulates gene transcription

Liver gene expression was examined in a “tx-j” mouse model of Wilson’s Disease caused by a mutation in ATP7B.  ATP7B secretes excess copper into the bile.  Non functional in WD patients have a toxic overload of copper in their livers.  Shibata and  coauthors [5] looked at gene expression (Y-axis, Fig 5A) for many stages of development.  They were particularly interested in genes that regulate DNA methylation.  We will stick to our story line and single out two genes that might impact fatty liver disease.

Figure 5 How copper might regulate fatty liver disease A. Relative expression between two select genes in control mice and a mouse model of Wilson’s disease B. Re-visitation of Figure 1 with gene expression data

We have no way of knowing if dietary copper of any sort mimics the effect of ATP7B defect (tx-j) copper overload.  In such a hypothetical methioinine synthase compensates for reduced dietary methione and possibly even choline.  By most accounts, S-adenosyl homocyetinase merely speeds up the equilibrium between homocysteine and S-adenosyl homocysteine.  The expression of this gene is decreased by copper overload.

Could Cu(I)NA2  regulate gene expression in the fatty liver in a manner that facilitates fat export?  We do not know! A certain amount of caution needs to be used that genes are over-expressed when there is too much copper are not expressed enough when there is copper deficiency.

Concluding remarks

  •   This featured Cu(I)NA2 study [1] was not concerned with enzymes involved with fatty liver disease.  The lessened liver damage and positive oxidative status results are the encouraging focus of this report.
  • Dietary deficiency in choline/methionine can impact can lead to fatty liver disease in dairy cattle [2].
  • Earlier rodent studies suggest a link between copper and the methionine cycle [3] .  Twenty years later there is no evidence that copper is a cofactor in methionine synthase.  Considering how magnesium does fit into the structure [4], it would be interesting if it did.
  • The most likely explanation for Reference [3] data is copper regulation of hepatic gene transcription, in particular methione synthase [5].
  • We want to emphasize that we are not making medical claims regarding Cu(I)NA2 in this post.  
  • We do see enough data to support investigative studies.


  1. Hegazy AM, Farid AS, Hafez AS, Eid RM, Nasr SM. (2019) Hepatoprotective and immunomodulatory effects of copper-nicotinate complex against fatty liver in rat model. Vet World. 12(12):1903-1910. [PMC free article]
  2. Abbasi, I.H.R., Abbasi, F., Soomro, R.N. et al. Considering choline as methionine precursor, lipoproteins transporter, hepatic promoter and antioxidant agent in dairy cows.(2017) AMB Expr 7, 214 (2017). [Cross Ref]
  3. Tamura T, Hong KH, Mizuno Y, Johnston KE, Keen CL. (1999) Folate and homocysteine metabolism in copper-deficient rats. Biochim Biophys Acta. 1427(3):351-6.
  4. González B, Pajares MA, Hermoso JA, Guillerm D, Guillerm G, Sanz-Aparicio J (2003) Crystal structures of methionine adenosyltransferase complexed with substrates and products reveal the methionine-ATP recognition and give insights into the catalytic mechanism. J. Mol. Biol. 331 407-16
  5. Le A, Shibata NM, French SW, Kim K, Kharbanda KK, Islam MS, LaSalle JM, Halsted CH, Keen CL, (2014)Characterization of timed changes in hepatic copper concentrations, methionine metabolism, gene expression, and global DNA methylation in the Jackson toxic milk mouse model of Wilson disease. Medici V. Int J Mol Sci. 2014 May 7;15(5):8004-23. [Cross Ref]

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