Lessons from a Wilson’s Disease mouse model
Wilson’s Disease is an affliction of not being to export copper due to mutations in the ATP7B Cu+ transporter. This study asked the question of how copper in the proper oxidation state affect the health hazards of a high fat Western Diet (WD) versus the normal control (NC) diet. This study utilized wild type mice and those same C57BL/6 mice with the ATP7B gene knocked out (ko)
The Western Diet from Research Diets (D12079B ) contained, per kg, 350 g sucrose, 50 g corn starch, 200g butter,
Figure 1A-D
After 9 weeks on the WD vs NC diet, the mouse weight gain was statistically the same regardless of the diet, ATP7B status. The male mice gained weight faster. The percentage body fat was a different matter. When on the Western Diet, both male and female wildtype mice accumulated more fat than their ATP7B knockout counterparts.
Figure 2
The Western diet increased serum glucose and cholesterol, but not serum triglycerides. Liver triglyceride content was increased by the Western diet. Serum glucose was lower in the TAP7B knockout mice than the wildtypes on the control diet. The Oil red O staining of fat in the liver was telling.
Stearoyl CoA desaturase (SCD) is an enzyme that uses O2 and electrons from reduced cytochrome b5 to introduce double bonds in the delta-9 of acyl-CoA substrate. Β-hydroxy-β-glutaryl CoA is an intermediate in the mevalonate pathway that ultimately leads to cholesterol synthesis. These pathways share NADPH as an intermediate.
Data are from Gottleib 2022 Figures 4 and 5 are not shown in this post. Much of this post is skipping the metabolic pathway ontology of Gottleib 2022 just because it highlights global clusters of enzymes and not ones that specifically use NAD derivatives. We’ve shown one. The take home theme does seem to be that fats accumulate in the liver because they are not used to produce cholesterol, a process that requires NADH.
Obviously too much of anything is toxic. While Cu+ entered the cells of the ATP7B knock out (ko) mice in this study via normal pathways, it built up to toxic levels. [1] Int is interesting to note that copper toxicity cancelled Western diet toxicity. How much could Cu+ improve the toxicity of the Western diet with functioning ATP7B?
References
- Gottlieb A, Dev S, DeVine L, Gabrielson KL, Cole RN, Hamilton JP, Lutsenko S. (2022) Hepatic Steatosis in the Mouse Model of Wilson Disease Coincides with a Muted Inflammatory Response. Am J Pathol. 2022 Jan;192(1):146-159.
Cuprous niacin 