Is PKD a metabolic problem at the cellular level?

Sometimes smaller studies are overlooked, especially where they don’t lead to the promise of an imminent breakthrough in the management of PKD.
One such was published on EbioMedicine in March of this year, with the factual, but dull, title: “Fatty Acid Oxidation is Impaired in An Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease”.   Rather pleasingly it is published under Creative Commons licence and open access – so anyone can go to the original paper.

I will come back to the detail of the paper in a while, but the highlight that caught my attention was the sentence:

Lower lipid content in diet correlates with slower PKD progression.

In fact this really pulled me up short – I love butter, not the pretend almost butter spreads, but real butter, thick on toast and jacket potatoes. Did I want to read this paper now if it might suggest I should cut down on butter? It is very easy to have an opinion and limit your research or reading to evidence supporting that viewpoint, so I pushed myself to reading the paper – several times because I knew the first read through I would only take in the negatives, I really don’t want my dietary equilibrium disturbed.

 

There are important qualifiers to this rather bold statement.
1. The study is in mice, specifically mice without the PKD1 gene (does it translate to humans and does it include PKD2 defects?)
2. The main aim of the study was to examine the lipid metabolic pathways in renal tubule cells from PKD1 mice, the dietary adjustment arm was an afterthought.
3. The low fat diet was actually given to the mothers of the baby PKD mice, so in some respects it is an indirect effect.
4. The fat content of the mouse chow was adjusted by very small amounts, from a 7.5% fat content to a 5.6% fat content.

So while mice can be fed a standardised diet with a fat content that is exactly the same day in day out, this is far harder to achieve in our own diets.

Is there any justification for eating less fat if you have PKD?

Some background

The working unit of a kidney is called a nephron, consisting of the glomerulus which filters the blood, the tubules that reabsorb electrolytes and get rid of toxins and the collecting ducts where some last minute fine adjustments are made before the urine moves along to the bladder.
The tubule epithelial cells need large amounts of energy to do their work and so they have developed the ability to take up fatty acids as an energy source.
The oxidation of fatty acids yields far more energy than that of carbohydrates (glucose).

Fat in the diet is emulsified and digested by enzymes in the gut, broken down into small chains and fatty acids so it can be absorbed. Actually once in the blood the components are resynthesized into triglycerides, easier to carry around in the blood in packages called lipoprotein complexes. But to be useful to the cells they have to be broken up again into fatty acids and glycerol. The glycerol goes off to the liver to be recycled while the fatty acids are transported into the cells via membrane proteins, to the mitochondria. Mitochondria look rather like miniature sea puddings inside the cells, they are the energy powerhouses. Renal tubule cells have lots of mitochondria.

image

Sea pudding

image

Mitochondria in renal tubule cell (nephrotube.blogspot.com) 

 

 

The genes responsible for ADPKD (PKD1 and PKD2) were discovered some 20 years ago but despite this the detailed functions of the polycystin proteins are still unknown. It is thought that they work together, as a membrane sensor and transporter, trafficking signals to the primary cilium.

 

The Study 

The researchers for this study were looking for differences in cell metabolism in PKD renal tubule cells compared with normal renal tubule cells. The paper goes into painstaking detail on the methods, most of which went over my head. The bottom line is that this was a cellular study in a Petri dish or two, and the results suggested that kidney cells from the PKD mice had an impairment in their ability to use fatty acids for energy.

Other studies have proposed that glucose metabolism is impaired in PKD, but this one showed no differences in the glucose pathways, just a reduced ability of the PKD tubule cells to metabolise fats.
The results strongly suggest that altered lipid metabolism, an intrinsic dysfunction in fatty acid oxidation in the renal tubular cells is one of the pathological processes in PKD.

It also outlines sex as a determinant of cyst severity. The male tubule cells were less able to utilise fatty acids than the female tubule cells which correlated with more severe cystic disease in the male mice. This finding is consistent with observations in humans that males tend towards worse cystic disease in the kidneys compared with females (with a reverse effect when it comes to liver cysts)

If lipid metabolism plays a role in cyst development then it was a reasonable step to try manipulating the fat content of the diet in these mice and relate that to the cyst size. I couldn’t work out from the method section just how many mice they used for this part of the study, but it appears they used juvenile mice and fed the two diets to the nursing mothers. I would be interested to see if this is reproducible in adult PKD mice, though my family can be reassured my interest is restricted to the theory and not experimental.

The theory behind this study, that one of the underlying defects in PKD is a problem with cell metabolism, is consistent with other research. For example, metformin and rapamycin, both shown to slow cyst growth, are drugs known to have significant metabolic effects. It is believed that the primary cilium in cells plays a role in regulating cell metabolism and known that in PKD their are problems with this ciliary signalling. So it does look as if altered cellular metabolism could have an effect on cyst development.

As I said at the beginning though, it is a relatively small study, and a little early to jump to conclusions about the role of diet in disease progression.
For me, this study is insufficient evidence to stop eating butter – I did say I would take some convincing!

I accept, however, that I cannot be complacent and further studies on cellular metabolism in PKD might result in stronger dietary guidelines.

 

References:
http://www.sciencedirect.com/science/article/pii/S2352396416300238
Menezes L, Lin C, Germino G. 2016 Fatty acid oxidation is impaired in an ortholagouse mouse model of autosomal dominant polycystic kidney disease. EBioMedicine March 2016, Vol5:183-192

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