LiSyM Researches How Genes Impact NAFLD
Professor Dr. med. Frank Lammert has been studying the genetics of liver diseases, including NAFLD, for more than 10 years now. “We have observed many individual differences in the development and progression of these diseases that cannot be explained by external factors,” says Lammert, who is a researcher in LiSyM as well as the director of the Department of Internal Medicine of the Saarland University Medical Center in Homburg. External factors causing NAFLD can be found primarily in the lifestyle in industrial countries where the high calorie Western diet is considered to be a decisive risk factor for many metabolic disorders like NAFLD. “However, genes are also important factors of influence,” Lammert says.
PNPLA3 promotes the onset and severe progression of fatty liver disease
Systems medicine experts currently know more about the effect of the gene PNPLA3 on NAFLD than they do about any other gene. In humans, this gene encodes the enzyme patatin-like phospholipase domain-containing protein 3, which is also known by other names, including adiponutrin. This enzyme is associated with lipid droplets and catalyzes the hydrolysis of triglycerides. Many people have the point mutation I148M in their PNPLA3 gene. “This is a common allele,” Lammert says, adding: “About 50 percent of the European population carry it. About 5 percent are even homozygous, meaning they have it double.”
In the case of I148M, the exchange of one letter in the genetic alphabet changes the amino acid in position 148 of the PNPLA3 enzyme. “This variant promotes the onset of fatty liver diseases as well as an unfavorable progression,” says the expert. It doubles the risk of developing NAFLD and triples the risk of steatohepatitis (NASH). The probability of developing liver fibrosis, liver cirrhosis, and a hepatocellular carcinoma (HCC) – regardless of whether the patient has alcoholic or non-alcoholic fatty liver disease – increases by more than 50 percent.
How PNPLA3 can affect this is currently being modeled by LiSyM researchers. The protein is found in hepatocytes (epithelial cells which make up approximately 80 percent of the liver volume) and adipocytes (fat cells). It is believed to be involved in regulating lipolysis (the breaking down of fats) and lipogenesis (fat production). Other genetic risk factors such as MBOAT7, which LiSyM also studies, modulate the effect of PNPLA3.
Genetic predispositions found for all stages and complications
According to Lammert, “Genetic predispositions have been identified for all stages and complications.” There are indications that genetic predisposition can influence certain stages of NAFLD for more than a dozen genes. “We want to treat patients with high-risk variants preventatively as early as possible,” the department director says. Doctors could monitor these high-risk patients more specifically, and they could initiate treatments at exactly the right time – for example, when their condition begins to worsen – not when it has already worsened. “To do this, we must continually better understand the progression of this disease with the help of model systems,” Lammert says.
Lammert believes that the best way to optimize and personalize the diagnosis, the monitoring of disease progression, as well as preventive therapy is to conduct large-scale clinical studies that combine research findings from clinical practice, modeling molecular phenotypes, and sequencing the entire genomes of patients. “This means we need adequate resources, which we must focus efficiently,” Lammert says. Knowledge of the genetics of NAFLD is currently being used primarily in experiments and pilot studies. However, Lammert points out that genetic research has also inspired new ideas for therapies, as can be seen with the NOD2 gene.
NOD2 variants increase the risk of mortality in patients with cirrhosis
Together with Dr. med. Matthias Christian Reichert, a senior physician at the Department of Internal Medicine, Lammert recently published a study on how variants of NOD2 (nucleotide-binding oligomerization domain 2) affect cirrhosis1. The study shows that NOD2 risk variants make patients with liver cirrhosis more susceptible to bacterial infections that occur frequently and are life-threatening. In cirrhosis patients, they often contribute to the onset of acute-on-chronic liver failure (ACLF). Bacterial infections can also induce threatening complications during ACLF.
When ACLF occurs, the mechanisms that restore and repair the liver in chronic diseases or in the case of cirrhosis are suddenly no longer sufficient. This decompensation leads to organ failure. Mortality increases dramatically – and rises even more if bacterial infections, such as peritonitis (infection of the membrane lining the abdominal cavity), occur. “Patients with certain NOD2 variants are at an especially high risk for this,” says Lammert, who posed the question: “Perhaps, in their case, bacteria can penetrate the intestinal wall more easily?” Bacteria causing peritonitis often originate in the intestines.
Like all other patients, those with unfavorable NOD2 variants currently often receive antibiotics if they contract an infection. “We are now trying to lower the tendency to develop an infection drastically using derivatives of bile acid,” says Lammert. Patients tolerate this medication better. However, Lammert is motivated by further challenges: “We want to suppress these infections and avoid acute-on-chronic liver failure!”
New approaches for high-risk patients
Unfortunately, there are still countless questions regarding these and many other points – for example, concerning HCC. “We can only stand by and watch,” says the department director, regretfully. Researchers posit that seriously ill patients often reach a kind of turning point, after which the infection inevitably develops into cancer. “We have not yet sufficiently defined this point,” Lammert says. This leaves questions such as: Which gene variants distinguish these patients? What were the specific precursory conditions dominating in their livers? “This is something we need to research,” says Lammert, adding: “After all, we all want to reach a point when HCC does not occur in the first place.” LiSyM initially did not study cancer, but now scientists in LiSyM are working hard in this field and plan to continue this line of research. “We recently submitted a grant application for this,” Lammert says, pointing out: “The systems medicine research of liver diseases has made many advancements possible, but we are far from realizing its full potential.”
Reichert, MC, Ripoll, C, Casper, M, Greinert, R , Vandieken, E, Grunhage, F, Appenrodt, B, Zipprich, A, Lammert, F (2019) Common NOD2 Risk Variants as Major Susceptibility Factors for Bacterial Infections in Compensated Cirrhosis. Clinical and Translational Gastroenterology 2019;10:1–9.
The three research areas of LiSyM: The development, progression, and complications of disease
The genetic research done in LiSyM can be categorized into three research areas. The first focuses on the development of NAFLD. “Some people are much more likely to develop a fatty liver due to their genetic profile,” explains the professor of medicine Dr. Frank Lammert. For example, in addition to PNPLA3, variants of the genes TM6SF2 and MBOAT7 are contributing factors.
The second area of research addresses the progression of disease. “Certain patients are more likely to develop NASH than others who are in a comparable state,” says Lammert. For these patients, gene variants are once again responsible for creating favorable conditions for the progression of the disease to steatohepatitis. Other gene variants, like those of the NOD2 gene, have a negative effect by enhancing the risk of developing complications and infections.
“Genes can also change the transport and breakdown of pharmaceutical and toxic substances in the liver, thereby influencing how effective a therapy will be,” Lammert says, naming the liver’s transporter gene ABCB4, which Dr. Ersin Karatayli is studying in Lammert’s research group, as an example. Fluctuations in the metabolism of substances can enhance, weaken, shorten, or lengthen certain effects. Side-effects can also be stronger. In the worst case, medications that would otherwise not pose a risk can cause serious damage in the already damaged organ of NAFLD patients. That is why the network’s third area of research is on the importance of genetics for patient responsiveness to new therapies.
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