Scientists discovered that a protein called GPR75 plays a major role in making fatty liver disease worse. When people have metabolic dysfunction-associated steatohepatitis (MASH)—a serious type of fatty liver disease—this protein increases significantly in their livers. In mouse studies, removing this protein protected the liver from fat buildup and damage, while adding more of it made the disease worse. The researchers found that GPR75 works by controlling how much fat the liver makes. This discovery suggests that blocking this protein could become a new treatment for fatty liver disease, which affects millions of people worldwide.

The Quick Take

  • What they studied: How a specific protein called GPR75 affects the development and worsening of fatty liver disease, particularly a severe form called MASH
  • Who participated: Laboratory mice were used in this study. Some mice were genetically modified to remove the GPR75 protein, while others had extra amounts of it. All mice were fed a diet designed to cause fatty liver disease
  • Key finding: Mice without the GPR75 protein developed significantly less liver fat and damage compared to normal mice, while mice with extra GPR75 developed worse disease. This suggests GPR75 is a key driver of fatty liver disease progression
  • What it means for you: This research suggests that medications designed to block or reduce GPR75 could potentially treat fatty liver disease in humans. However, this is early-stage research in animals, and human studies would be needed before any new treatment becomes available

The Research Details

This was a laboratory research study using genetically modified mice to understand how a specific protein affects fatty liver disease. The researchers created three groups of mice: some with the GPR75 gene removed entirely, some with the gene removed only in liver cells, and some with extra copies of the gene. All mice were then fed a high-fat diet to trigger fatty liver disease, and the researchers compared how the disease developed in each group.

The scientists also studied the molecular mechanisms—essentially the step-by-step chemical processes—that explain how GPR75 causes problems. They examined which other proteins and signaling pathways were activated or deactivated when GPR75 was present or absent. This involved analyzing liver tissue samples and measuring various markers of liver health and fat production.

The research team used advanced laboratory techniques to track how GPR75 protein is recycled and moved around within liver cells, and how this affects the cell’s ability to make and store fat.

This research approach is important because it identifies a specific molecular target that could be used to develop new treatments. By using genetically modified mice, researchers can determine whether a protein directly causes disease or just appears alongside it. This type of evidence is crucial for deciding whether blocking this protein would actually help patients. The study also reveals the exact biological mechanisms involved, which helps scientists design drugs that specifically target this pathway without causing unwanted side effects

This study was published in Hepatology, a highly respected scientific journal focused on liver disease research. The research used standard laboratory methods and included multiple experimental approaches to verify findings. However, this is animal research, which means results may not directly translate to humans. The study did not specify the exact number of mice used, which would be helpful for understanding the statistical strength of the findings. Additional human studies would be needed to confirm these results apply to people with fatty liver disease

What the Results Show

When researchers removed the GPR75 gene from mice, the animals developed significantly less liver fat and showed less liver damage when fed a high-fat diet. This protective effect occurred whether the gene was removed from all liver cells or just from the main liver cells called hepatocytes. In contrast, when mice were given extra copies of the GPR75 gene specifically in hepatocytes, they developed worse fatty liver disease and more liver scarring (fibrosis) compared to normal mice on the same diet.

The researchers discovered that GPR75 works by controlling how much fat the liver produces. When GPR75 was absent, the liver activated a protective signaling pathway called GNAI2-cAMP-PKA. This pathway reduced the activity of a key protein called SREBP-1c, which is responsible for telling the liver to make new fat. With less SREBP-1c activity, the liver made significantly less fat.

The study also revealed how GPR75 protein is maintained in liver cells. A protein called VPS35 acts like a recycling system, keeping GPR75 on the cell surface where it can do its job. This recycling process prevents GPR75 from being broken down and removed from the cell, allowing it to continue promoting fat production.

The research showed that GPR75 levels are normally very low in healthy livers but increase dramatically when fatty liver disease develops. This suggests the body may be responding to disease conditions by producing more of this harmful protein. The study also demonstrated that the GNAI2-cAMP-PKA signaling pathway is a key protective mechanism that becomes activated when GPR75 is removed, suggesting this pathway could be another potential treatment target

This research identifies GPR75 as a previously unknown player in fatty liver disease. While scientists have studied many proteins involved in liver fat metabolism, GPR75 had not been recognized as important in this disease. The findings build on existing knowledge about how the liver controls fat production through various signaling pathways. The discovery that VPS35 recycles GPR75 adds to our understanding of how proteins are managed within cells and how this management affects disease

This study was conducted entirely in laboratory mice, not in humans, so results may not directly apply to people with fatty liver disease. The study did not specify how many mice were used in each experiment, making it difficult to assess the statistical reliability of the findings. The research focused on one specific protein pathway and may not account for other factors that contribute to fatty liver disease in humans, such as genetics, diet quality, exercise, and other medical conditions. Additionally, the study used a specific type of high-fat diet in mice, which may not perfectly replicate how fatty liver disease develops in humans with varied diets and lifestyles

The Bottom Line

Based on this research, blocking or reducing GPR75 appears promising as a potential treatment strategy for fatty liver disease. However, this is early-stage research, and the confidence level is moderate because it has only been tested in animals. Before any new treatment could be recommended for patients, human clinical trials would be necessary to confirm safety and effectiveness. Currently, the best-established approaches for managing fatty liver disease remain weight loss, regular exercise, and dietary improvements

This research is most relevant to people with fatty liver disease (MASLD or MASH), their doctors, and pharmaceutical companies developing new treatments. People with metabolic syndrome, obesity, type 2 diabetes, or high cholesterol should be aware of this research since these conditions increase fatty liver disease risk. However, this research should not change anyone’s current treatment plan until human studies are completed and new medications become available. People without fatty liver disease do not need to take action based on this research

If this research leads to drug development, it typically takes 5-10 years or more before a new treatment becomes available to patients. This includes laboratory testing, animal studies (which are now underway), human safety trials, and regulatory approval. People with fatty liver disease should continue following their doctor’s current recommendations while waiting for potential new treatments to be developed

Want to Apply This Research?

  • Users with fatty liver disease could track liver health markers by recording their ALT and AST enzyme levels (measured through blood tests) every 3-6 months, along with their weight and waist circumference weekly. This creates a measurable record of disease progression or improvement
  • While waiting for potential GPR75-targeting treatments, users should focus on proven interventions: log daily steps to aim for 150 minutes of moderate activity weekly, track daily food intake to identify high-fat foods to reduce, and monitor weight loss progress (even 5-10% weight loss can significantly improve fatty liver disease)
  • Set up quarterly reminders to schedule liver function blood tests with their doctor. Use the app to track the trend of these results over time. Additionally, maintain a monthly check-in on weight, energy levels, and any symptoms. This long-term monitoring helps users and their doctors assess whether current lifestyle changes are working and whether new treatments should be considered when available

This research describes early-stage laboratory findings in mice and does not represent approved medical treatment for humans. Fatty liver disease is a serious medical condition that requires professional medical evaluation and management. If you have been diagnosed with fatty liver disease or MASH, consult with your healthcare provider before making any changes to your treatment plan. This article is for educational purposes only and should not be used as a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified healthcare provider with any questions you may have regarding a medical condition.