Nicotinamide Riboside + Ketogenic Diet for Fatty Liver Disease

Overseen By Stephanie T Chung, M.D.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Must not be taking: Diet medications

Disqualifiers: Liver disease, Non-MODY2 diabetes, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how a low-carb ketogenic diet and a supplement called nicotinamide riboside (NR) can enhance the body's ability to use fat efficiently. Fatty liver disease, characterized by excessive fat storage in the liver, currently relies on lifestyle changes for treatment. The study aims to determine if these new approaches can improve energy use and fat burning. Men and women who are overweight or have a specific type of diabetes (MODY2) and maintain stable weight might be suitable candidates for this trial. Participants will follow different diets and undergo various tests to measure their body's response. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could lead to new treatment options.

Will I have to stop taking my current medications?

Yes, participants must stop taking prescription medications or other drugs or supplements that may affect energy metabolism or nutrient digestion or absorption.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that nicotinamide riboside (NR) is generally safe and approved for use in food products in the United States. Studies have tested NR at doses up to 3000 mg per day with proper safety checks, indicating it is well-tolerated. However, concerns exist about the risks of using high doses for extended periods.

Regarding the ketogenic diet, research suggests it can help treat fatty liver disease, though results are mixed. Some studies in mice have shown that a very high-fat, low-carb diet might cause liver problems over time. In humans, however, the diet usually has positive effects on liver health when properly monitored.

In summary, studies have shown that both NR and the ketogenic diet are safe, but careful monitoring and moderation remain important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the Nicotinamide Riboside (NR) and Ketogenic Diet combination for fatty liver disease because it offers a fresh approach by potentially boosting energy expenditure and fat oxidation, particularly during sleep. Unlike typical treatments that might focus on reducing liver fat through medications or lifestyle changes, this combination targets the body's metabolism at a cellular level with NR, a form of vitamin B3, and leverages the high-fat, low-carb ketogenic diet to enhance these effects. This dual approach could lead to more efficient fat burning and energy use, which are promising for managing and possibly improving fatty liver conditions.

What evidence suggests that this trial's treatments could be effective for fatty liver disease?

Research has shown that nicotinamide riboside (NR), a type of supplement, may help with liver issues. Studies in mice found that NR improves sugar metabolism and reduces liver damage and fat buildup. It also seems to protect against liver fat and may even reverse some fatty liver conditions. In this trial, some participants will receive NR supplementation.

Research has also shown that a ketogenic diet, very low in carbohydrates and high in fats, can effectively reduce liver fat. This diet lowers liver inflammation and improves overall liver health. Participants in this trial will follow a ketogenic diet to assess its effects on liver health.

Together, these treatments might offer new hope for people dealing with fatty liver disease, and this trial will explore their combined effects. ^{1 2 5 6 7}

Who Is on the Research Team?

Stephanie T Chung, M.D.

Principal Investigator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Are You a Good Fit for This Trial?

This trial is for healthy men aged 18-65 and pre-menopausal women aged 18-50 with a BMI of 25 or more, including those with MODY2 diabetes. Participants should be weight stable and able to perform moderate cycling without heart issues. Exclusions include heavy alcohol use, liver disease indicators, significant medical conditions, drug use, certain psychological conditions, strict dietary restrictions, inability to follow study procedures or give consent.

Inclusion Criteria

Able to cycle at a moderate rate and intensity with a HR equal to or greater than 0.3(SqrRoot) (220-age-HRest)+HRest but not exceeding 0.4(SqrRoot) (220-age-HRest)+HRest with no signs of arrhythmia

I am an adult with MODY2, male (18-65) or female (18-50) and not in menopause.

I am a woman aged 18-50 and have not gone through menopause.

Exclusion Criteria

My hematocrit level is below 37%.

You are currently involved in a regular exercise program, doing more than 2 hours of intense activity each week, as reported by you.

You drink more than 300 mg of caffeine per day, according to what you tell us.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Baseline Diet

Participants consume a standard high-carbohydrate diet to establish baseline measurements

2 days

Part of clinic stay

Ketogenic Diet with NR or Placebo

Participants consume a ketogenic low-carb diet for 5 days, with healthy volunteers taking NR or placebo

5 days

Part of clinic stay

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ketogenic Diet
• Nicotinamide Riboside
• Placebo
• Standard Diet

Trial Overview The trial examines the effects of a ketogenic diet and nicotinamide riboside (NR) supplement on fat usage in the body. Healthy volunteers will take NR pills for two weeks during one clinic stay and placebos during another. All participants will switch from a standard American diet to a low-carb ketogenic diet while undergoing various tests like physical exams, blood/urine tests, activity monitoring, glucose level tracking and imaging scans.

How Is the Trial Designed?

Group I: Women with overweight or obesity Experimental Treatment 4 Interventions

To investigate whether NR supplementation augments the sleeping energy expenditure and fat oxidation rate during the ketogenic diet in men and women with overweight and obesity

Group II: Men with overweight or obesity Experimental Treatment 4 Interventions

To investigate whether NR supplementation augments the sleeping energy expenditure and fat oxidation rate during the ketogenic diet in men and women with overweight and obesity

Group III: MODY2 Patients Experimental Treatment 3 Interventions

To measure changes in sleeping energy expenditure and fat oxidation rate after transitioning from a baseline diet to an isocaloric ketogenic diet similar to our previous study in men

Who Is Running the Clinical Trial?

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Lead Sponsor

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

Nicotinamide riboside (NR) supplementation significantly reduced liver fibrosis in a diet-induced mouse model, indicating its potential as a preventative treatment for liver fibrosis associated with non-alcoholic fatty liver disease (NAFLD).

NR was found to inhibit the activation of hepatic stellate cells, which play a key role in liver fibrosis, and also increased energy expenditure, suggesting a mechanism of action that may involve enhancing metabolic processes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside, an NAD+ precursor, attenuates the development of liver fibrosis in a diet-induced mouse model of liver fibrosis. Pham, TX., Bae, M., Kim, MB., et al.[2021]

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing alongside obesity and metabolic syndrome, making it the most common chronic liver disease, which can progress to severe conditions like cirrhosis and liver cancer.

A ketogenic diet (KD), which is very low in carbohydrates, may help alleviate oxidative stress and restore mitochondrial function, suggesting it could be a potential therapeutic approach for managing NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating the Link between Ketogenic Diet, NAFLD, Mitochondria, and Oxidative Stress: A Narrative Review. Paoli, A., Cerullo, G.[2023]

In a study of 153,076 nondiabetic Koreans followed for an average of 4.1 years, fasting ketonuria was linked to a significantly lower risk of developing nonalcoholic fatty liver disease (NAFLD), with a hazard ratio of 0.81 compared to those without ketonuria.

Persistent ketonuria was associated with the greatest reduction in risk for incident hepatic steatosis, suggesting that higher levels of ketones may play a protective role against liver fat accumulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fasting Ketonuria and the Risk of Incident Nonalcoholic Fatty Liver Disease With and Without Liver Fibrosis in Nondiabetic Adults. Kim, Y., Chang, Y., Kwon, MJ., et al.[2021]

The Spanish Ketogenic Mediterranean Diet (SKMD) significantly improved various health markers in 14 obese men over 12 weeks, including body weight, liver enzymes, and cholesterol levels, indicating its efficacy in treating metabolic syndrome (MS) and nonalcoholic fatty liver disease (NAFLD).

After following the SKMD, all participants were free of metabolic syndrome according to the International Diabetes Federation criteria, demonstrating the diet's potential as a safe and effective intervention for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of the Spanish Ketogenic Mediterranean Diet on nonalcoholic fatty liver disease: a pilot study. Pérez-Guisado, J., Muñoz-Serrano, A.[2017]

Hypocaloric diets, especially low carbohydrate ketogenic diets, are effective in rapidly reducing liver fat and improving metabolic issues associated with non-alcoholic fatty liver disease (NAFLD).

Diets high in saturated fats are particularly harmful, as they increase liver fat and insulin resistance, while vitamin E supplementation can reduce liver fat and fibrosis but does not improve insulin resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance. Yki-Järvinen, H.[2018]

Weight loss of at least 5-7% of total body weight is crucial for improving liver health in patients with non-alcoholic fatty liver disease (NAFLD), as it can lead to better liver enzyme levels and reduced liver fat.

A hypocaloric diet is the most effective dietary approach for weight loss in NAFLD management, while a Mediterranean diet can also improve liver fat levels even without weight loss, highlighting the importance of personalized dietary recommendations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary Approaches for Management of Non-Alcoholic Fatty Liver Disease: A Clinician's Guide. Aboubakr, A., Stroud, A., Kumar, S., et al.[2021]

In a study of 70 diabetic patients with nonalcoholic fatty liver disease (NAFLD), nicotinamide supplementation (1000 mg daily for 12 weeks) significantly reduced liver enzymes and improved metabolic markers like cholesterol and insulin resistance, although it did not affect liver steatosis or fibrosis scores.

Patients taking nicotinamide also reported a significant improvement in their quality of life, particularly in areas related to activity and fatigue, indicating that while it may not change liver fat levels, it can enhance overall well-being.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide supplementation in diabetic nonalcoholic fatty liver disease patients: randomized controlled trial. El-Kady, RR., Ali, AK., El Wakeel, LM., et al.[2022]

Nicotinamide riboside (NR) has been shown to prevent and even reverse liver fibrosis in mice, indicating its potential as a protective treatment against liver damage.

The protective effects of NR are linked to its ability to activate Sirt1, which regulates the acetylation of Smads, thereby inhibiting the activation of hepatic stellate cells involved in liver fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside protects against liver fibrosis induced by CCl4 via regulating the acetylation of Smads signaling pathway. Jiang, R., Zhou, Y., Wang, S., et al.[2022]

In a pilot study of 5 patients with obesity-related fatty liver disease, a low-carbohydrate ketogenic diet for 6 months resulted in an average weight loss of 12.8 kg, indicating its potential effectiveness for weight management.

Post-treatment liver biopsies showed significant histological improvements in liver fat content, inflammation, and fibrosis, suggesting that this dietary approach may help reverse fatty liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study. Tendler, D., Lin, S., Yancy, WS., et al.[2018]

In a study of 240 adults (120 with NAFLD and 120 without), low carbohydrate diets (LCDs) did not show a significant association with the risk of developing non-alcoholic fatty liver disease, suggesting that higher protein and fat intake alone may not contribute to NAFLD risk.

Patients with NAFLD had significantly higher intakes of protein, carbohydrates, and cholesterol compared to controls, indicating that while these dietary factors are prevalent in NAFLD, they do not correlate with the consumption of low carbohydrate diets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adherence to low carbohydrate diets and non-alcoholic fatty liver disease: a case control study. Yaghoubi, F., Darand, M., Vasmehjani, AA., et al.[2023]

In a study of 74 patients with non-alcoholic fatty liver disease (NAFLD), both the low-carb high-fat (LCHF) diet and the 5:2 intermittent calorie restriction diet significantly reduced liver fat and body weight compared to standard lifestyle advice, with reductions of 7.2% and 6.1% in hepatic steatosis, respectively.

There was no significant difference in effectiveness between the LCHF and 5:2 diets, indicating that both can be tailored to individual preferences for treating NAFLD, while the 5:2 diet also improved LDL cholesterol levels and was better tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet - a randomised controlled trial. Holmer, M., Lindqvist, C., Petersson, S., et al.[2022]

A 12-week clinical trial involving 40 obese, insulin-resistant men found that supplementation with nicotinamide riboside (NR) at a dose of 2000 mg per day was safe, with no serious adverse events reported.

However, NR supplementation did not improve insulin sensitivity or metabolic parameters such as glucose metabolism, resting energy expenditure, or body composition, indicating that it may not be effective for enhancing metabolic health in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Dollerup, OL., Christensen, B., Svart, M., et al.[2023]

The combination of L-carnitine and nicotinamide riboside significantly reduced body weight gain (by 17%) and fat mass gain (by 22%) in mice on a high-fat diet over 21 weeks, indicating its potential as an effective treatment for obesity and non-alcoholic fatty liver disease (NAFLD).

This combined treatment improved liver metabolism by reversing harmful effects of a high-fat diet on key metabolic pathways, suggesting a novel approach to enhance fatty acid utilization and protect against obesity-related liver damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis. Salic, K., Gart, E., Seidel, F., et al.[2021]

Citations

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Exploring the impacts of ketogenic diet on reversible ... In the present study, we evaluated the effect of dietary saturated fats contained in lard and the total absence of carbohydrate in KD (84,5% fat ...

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New Study in Mice Reveals Long-Term Metabolic Risks ... Research in mice shows dangerous consequences of a very high-fat, low-carb ketogenic diet. Keto was associated with fatty liver disease and ...

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A long-term ketogenic diet causes hyperlipidemia, liver ... Ketogenic diets (KDs)—very-low-carbohydrate and very-high-fat diets—have gained popularity as therapeutic against obesity and type 2 ...