Copper, fructose, and NAFLD

We at CopperOne are thinking that we should not forget the other pandemic: Non alcoholic fatty liver disease (NAFLD) According to the National Institute of Diabetes and Digestive and Kidney Diseases, about 24% of the US population have NAFLD. From 1.5 to 8.5% of the US population have non alcoholic steatohepatits. NASH exhibits inflammation in addition to the fat accumulation of NAFLD.

Dong-Mei Zhang, Rui-Qing Jiao, and Ling-Dong Kong of the State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University in China wrote an interesting review on the topic of fructose [1] that many would consider a poison of the Western diet. This post is devoted to keeping current with the copper and NAFLD literature in 2022. Fructose may be linked to NAFLD [1]

From Zang review [1] Our comments taken from the review in purple DHAP, dihydroxyacetone phosphate; TG: triglyceride; FFA: free fatty acid; UA: uric acid; MG: methylglyoxal; VLDL-TG: very low-density lipoprotein-TG. DNL: de novo lipogenesis. E1: Serine palmitoyltransferase; E2: 3-ketodihydrosphingosine reductase; E3: Ceramide synthase; E4: Dihydroceramide desaturase.

Fructose is absorbed by our GI epithelial cells via Glut5, transported into our circulation via Glut2, and absorbed into our livers via Glut5 again. [1] About half of the fructose we consume is metabolized via “frutolysis” by our livers. [1] Fructolysis products dihydroxy acetone and glyceraldehyde, a triglyceride precursor. [1] This process consumes 1 ATP. The Zhang review seemed to focus on reactive oxygen species (ROS), impairment of the electron transport chain, and general mitochondrial dysfunction. [1]

Normal rats on high fructose [2]

This study was a collaboration between the University of Alaska, Anchorage and Montana State University.  The study examined biochemical and metabolic parameters in rat chow

These formulations included diets containing

  • A Copper adequate 12.0 mg/kg Cu,
  • B Copper adequate plus drinking water with 30% w/v fructose
  • C Copper deficient <0.2 mg/kg Cu content, no fructose
  • D Copper deficient, with drinking water with 30% w/v fructose

Note, the Cu in the adequate diet according to supplemental table 1 contained 21 mg per kg “Cu carbonate” without specifying the oxidation state. Otherwise, minerals were supplied as an AIN salt mix without copper. Copper in the AIN salt mix is supplied as cupric carbonate. We at CopperOne have our disagreements with the oxidation state of the copper. While much can be said for a precise laboratory diet, nothing about this diet resembles how rats would be getting their copper in the wild. Rats were kept on this diet for five weeks. 

From ref [1]

In this table summarizing results A♀ is females on diet A, B♂ is males on diet B, and so on…

Serum Cu 
Hepatic Cu
Cp activity, serum
SSAO act, serum & liver
Complex IV, liver amount
Ctr1 liver
Summary of data from Morrell 2020 “-” indicates no significant change. Arrows indicate the direction of the significant change.

These data were extracted from hierarchical clustering data of figure 6.  The treatment groups were arranged to show the top 25 components common to males and females.  Only metabolites of interest of this website are shown.  NAD+ is the first to show a pattern of decreasing in the fructose loaded rats on a copper adequate diet.  Mitochondria going full throttle would be expected to increase NAD+ unless the TCA cycle was keeping up very well.  AMP would also be expected to decrease with an adequate supply of calories, especially with fully functional mitochondria.    

Note that in both females and males hepatic

  • NAD+ decreases with adequate dietary copper and high fructose.
  • AMP, an indicator of poor energy status, decreases probably because of the calorie load from the fructose, but only in the Cu adequate animals. [2]
  • Fumarate is an intermediate in the TCA cycle that produces NADH reducing equivalents for the electron transport chain.
  • Glucose is split to form pyruvate, prior to entering the TCA cycle as acetylCoA.
  • Pyruvate increases with the high fructose and copper adequate diets but not with the copper deficient high fructose diet.
And some numbers from the supplemental data section [2]
Supplemental data figures 9 and 10 highlights [1] with some images of metabolic pathways.

The above image was started with the most significant metabolic indicators in the female rats, Fig s9. Then the same indicators were selected from Fig s10. NAD was not an indicator in females; lactate was not an indicator n males. The most alarming indicator is the alanine found to be elevated in mice of both genders. Are their muscles being broken down in a vain attempt to generate glucose?

The Morrell study seemed to indicate that a “copper adequate” diet was worse than a copper deficient diet when it comes to dealing with fructose liver toxicity. It should be remembered that these rats were getting the copper in the form of Cu(II) carbonate. We at CopperOne think of Cu(II) as “toxic copper.” The Zhang review {2] did review papers suggesting the role of electron transport chain defects and the reactive oxygen species super oxide. [2] CopperOne’s response would be that Cu/Zn superoxide dismutase and mitochondrial cytochrome C oxidase receive their Cu from Cu(I) carrying chaperones. We’d like to continue the work of Morrell and others [2] with proper copper. Excess fructose in the diet will perhaps always be considered toxic with or without proper CopperOne.


  1. Zhang DM, Jiao RQ, Kong LD. High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions. Nutrients. 2017;9(4):335. PMC free article
  2. Morrell, A., Tripet, B. P., Eilers, B. J., Tegman, M., Thompson, D., Copié, V., & Burkhead, J. L. (2020). Copper modulates sex-specific fructose hepatoxicity in nonalcoholic fatty liver disease (NALFD) Wistar rat models. The Journal of nutritional biochemistry, 78, 108316. PMC free article

Published by BL

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