Effects of Methylprednisolone Greatly Affected by Diet in SLE Mice

High-fat diet found to significantly lower effectiveness of corticosteroids

Patricia Valerio, PhD avatar

by Patricia Valerio, PhD |

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A study in a mouse model of systemic lupus erythematosus (SLE) showed that treatment with methylprednisolone significantly improves survival rates in animals fed a regular diet — but not among those given a diet high in fats, which instead lessened the beneficial effects of the corticosteroid. 

In fact, a diet with 60% fat significantly increased the incidence of severe proteinuria — high urine levels of protein, which might indicate alterations in kidney function — and blood sugar levels, suggesting intolerance for sugar processing.

In addition, treatment with methylprednisolone significantly decreased the blood levels of certain pro-inflammatory factors, but only in animals fed a regular diet. 

“These data improve our understanding of the effect of [high-fat diet] on the therapeutic efficacy of corticosteroids in SLE treatment, which could have clinical implications,” the researchers wrote.

The study, “Effects of high fat diet-induced obesity on pathophysiology, immune cells, and therapeutic efficacy in systemic lupus erythematosus,” was published in Nature Scientific Reports

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Undermining the effects of methylprednisolone

SLE is the most common form of lupus. This autoimmune disease may affect several systems in the body, including kidney, skin, and heart functioning. The type and severity of lupus symptoms and affected organs can influence the treatment for the disease. Methylprednisolone, a corticosteroid that tones down inflammation, is often used in the treatment of lupus patients. 

Previous studies have suggested that obesity and metabolic syndrome — a group of conditions that increase the risk of heart disease, stroke, and type 2 diabetes — are risk factors leading to inflammatory and autoimmune diseases.

“Prior studies have suggested a strong link between obesity and autoimmune diseases,” the researchers wrote. “However, there have been no specific studies on the effect of [high fat diet]-induced obesity on SLE treatment comprising corticosteroids.”

Now, researchers in the South Korea have investigated the effects of obesity caused by a high-fat diet on the development of the disease, in immune cell responses, and in the therapeutic efficacy of methylprednisolone in a mouse model of SLE.

Researchers fed two groups of SLE animals a regular diet with 10% fat. One of the groups was treated with methylprednisolone, while the other served as a control group and was given no treatment. A similar approach was taken for another two groups of mice given a high-fat diet with 60% fat — only one group received methylprednisolone.

When examining survival rates, the team found them to be significantly higher in the methylprednisolone-treated group fed a regular diet than in the treated group receiving a high-fat diet. The treated regular diet group also showed higher survival rates than those with the same diet but without methylprednisolone treatment.

In contrast, there was no significant difference in survival rates between mice receiving a high-fat diet with or without methylprednisolone treatment.

“In other words, methylprednisolone treatment significantly increased the survival rate under the control diet, but not under an [high-fat diet],” the researchers wrote.

At the kidney level, blood tests revealed the increased presence of severe proteinuria in mice fed a high-fat diet.

Other tests, including of blood urea nitrogen — a waste product kidneys remove from the blood and whose high levels can indicate kidney malfunction — and urinary protein to creatinine ratio, which tells how much protein is lost through the kidneys, showed kidney function improvements with methylprednisolone treatment. Lower levels were found regardless of the type of diet provided to the SLE mice.

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Regular diet improves methylprednisolone effects

In addition, the high-fat diet was found to significantly enhance the incidence of intolerance to sugar. In animals fed a regular diet, treated or not with methylprednisolone, the blood sugar levels were lower than in those provided a diet rich in fat, with or without treatment.

“An [high-fat diet] significantly increased the incidence of severe proteinuria and glucose intolerance,” the team wrote.

Cytokines — a group of small proteins critical for cell signaling — play a key role in inflammation and autoimmunity, including in lupus disease. Independently of the diet given, researchers found that methylprednisolone treatment significantly lowered the blood levels of a group of these proteins — namely interleukin (IL)-2, IL-10, and interferon gamma-induced protein 10 (IP-10, also known as CXCL10).

Other cytokine concentrations involved in promoting inflammation — IL-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-alpha) — also were decreased, however only in animals treated with methylprednisolone and fed a regular diet.

Also, regardless of the type of diet provided, the measured blood levels of anti-dsDNA antibodies, which indicate the presence of lupus, were lower in the two methylprednisolone-treated groups.

Together, the results strongly suggest that the type of diet can greatly affect the effect of methylprednisolone treatment.

“The results on the survival rate and occurrence of severe proteinuria in this study suggest that obesity induced by [high-fat diet] significantly reduced the therapeutic effect of methylprednisolone in SLE, in a process probably involving proinflammatory cytokines such as IL-6, MCP-1 and TNF-[alpha],” the researchers wrote.

Overall, the data obtained in this study with an SLE mouse model “may present significant translational potential for further understanding the effect of [high-fat diet] on the therapeutic efficacy of corticosteroids, which may help develop better therapeutic strategies based on dietary control,” the team concluded.