Tag: nonalcoholic fatty liver disease

Categories : Gastrointestinal Metabolic DisordersTags :

Targeting Inflammation may Not Help Reduce Liver Fibrosis in MAFLD

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Researchers at UCLA Health uncovered new information about the role inflammation plays in mitigating liver fibrosis, which is associated with metabolic-associated fatty liver disease (MAFLD).  While inflammation in the liver has long been considered a prerequisite to developing liver fibrosis, the scarring and thickening of tissue that can impair the liver’s ability to function, this new research, published in the Journal of Clinical Investigation, suggests that reducing inflammation may not influence the extent of fibrosis. 

“Liver fibrosis is the critical feature that creates chronic liver disease and liver cancer. If we can keep fibrosis in check then we can meaningfully impact liver disease,” said Tamer Sallam, MD, corresponding author of the study and vice chair and associate professor in the department of medicine at the David Geffen School of Medicine at UCLA. 

“For decades we have believed that targeting inflammation is one of the most important ways to reduce MAFLD. But this new research indicates that inflammation, while still important, may not be the main driver of fibrosis.”

The study looked specifically at a protein called lipopolysaccharide binding protein (LBP), which is involved in the body’s immune response, and how LBP functions in mice. Findings showed that mice without LBP in their liver cells had lower levels of liver inflammation and better liver function but no change in fibrosis. 

In addition to mouse models, the researchers also studied genetic analyses from large human datasets and human tissue samples from MAFLD patients at different stages in the disease, to examine the consequence of loss of LBP function. The evidence combined showed that the LBP does not alter scar tissue markers. 

Sallam indicated a need to further explore how LBP influences inflammation and whether other factors can offer a more potent reduction in inflammation and have an impact on reducing fibrosis. 

“Reducing scar burden is one of the holy grails in the treatment of advanced liver diseases,” Sallam said. “These results suggest that certain ways of targeting inflammation may not be a viable option and that more directed therapies against other pathways could help us better target fibrosis and improve outcomes for patients.”

Source: UCLA Health

Categories : Diseases, Syndromes and ConditionsTags :

Nonalcoholic Fatty Liver Disease Comes with an Increased Infection Risk

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A Swedish study of more than 12 000 patients with nonalcoholic fatty liver disease (NAFLD) revealed a significantly increased risk of severe infections requiring hospital admission. The study was published in Clinical Gastroenterology and Hepatology.

NAFLD is considered a manifestation of the metabolic syndrome in the liver and with the global rise in obesity, NAFLD has emerged as the most common chronic liver disease affecting around one quarter of all adults worldwide. Being such a wide-spread disease, it has also become the fastest growing cause of end-stage liver disease, primary liver cancer and liver transplantation. In recent years, NAFLD is increasingly viewed as a multifaceted disease affecting multiple organ systems.

In the ESPRESSO study, involving 12 133 individuals with biopsy-proven NAFLD, and 57 516 matched controls from the general population, NAFLD was associated with a 71% higher risk for severe infections requiring hospital admission. The researchers found that individuals with NAFLD exhibited the same spectrum of infection sites as compared with the general population – with respiratory and urogenital tract infections being the two most common sites of infection.

“Our work is important as the first nationwide study assessing the risk of infections in individuals diagnosed with NAFLD”, says lead author Dr Fahim Ebrahimi, MD, MSc, postdoctoral researcher at Karolinska Institutet and gastroenterologist at Clarunis University Center for Gastrointestinal and Liver Diseases in Basel, Switzerland. “Our findings highlight the importance of NAFLD as a multisystem disorder that increases the risk of infections independent from other underlying risk factors such as diabetes mellitus.”

Risk differences for infections

The researchers were intrigued by previous experimental studies that suggested that NAFLD is associated with impaired function of several immune cells which may lead to higher susceptibility towards various viral, bacterial, and fungal infections. “The liver plays a significant role in the human immune system with immune cells, such as macrophages (Kupffer cells) and lymphocytes, constituting up to 20% of all liver cells”, adds Dr. Ebrahimi. “We were surprised to find that the risk of severe infections was increased even in people with simple fatty liver disease without evidence of any liver inflammation or fibrosis. However, when individuals had evidence of the inflammatory subtype nonalcoholic steatohepatitis (NASH), or had developed fibrosis, they were at even higher risks with the highest risks among those with cirrhosis.”

“The absolute risk difference at 20 years after NAFLD diagnosis was 17.3%, equal to one extra severe infection in every 6 patients with NAFLD, therefore, our findings underline the importance of early diagnosis and treatment to reverse the disease at all stages”, says corresponding author Jonas F Ludvigsson, paediatrician at Örebro University Hospital, and professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.

“To date, clinical guidelines on NAFLD have not yet included specific recommendations for preventing and managing infections”, says Dr Ebrahimi. “Based on our results, prevention of infections should become one of the main public health efforts to tackle NAFLD associated morbidities.”

Source: Karolinksa Insitutet

Categories : GenderTags :

Selection for Metabolism and Immunity Explains Fatty Liver Sex Differences

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Anatomy of the gut
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A new way of understanding sex-biased diseases has been developed by scientists at UC San Francisco (UCSF). Their evolutionary biology-based theory, published in in Science, is that males and females took opposing paths in a trade-off between immunity and metabolism that happens in the liver. This helped males fight bacterial infections from wounds received in dominance fights, while helping females store subcutaneous fat to survive when food is scarce.

Working with mice, the scientists described the activity of a signalling pathway that regulates lipids, storing fat in the liver in males and releasing it into the bloodstream in females. This pathway also responds to growth hormone.

This phenomenon may have shaped male biology in ways that increase risk from modern, high-calorie diets. The findings are particularly important for fatty liver, which affects a quarter of the US population. It is seen predominantly in men until women reach menopause.

“Scientists have only recently started to understand there are these profound differences between males and females,” said Holly Ingraham, PhD, UCSF professor and co-senior author of the study. “Understanding these differences is going to be the key to unlocking therapeutics for sex-biased diseases. Fatty liver is one example.”

The experiments found that male mice were three times more likely than females to survive infection with E. coli. The females developed hyperlipidaemia, a condition that is also seen in humans with severe sepsis. Lowering their lipid levels helped them to survive.

The investigators then examined how males and females respond to the contemporary environmental challenge of overeating by feeding the mice high-fat chow. males developed fatty liver and glucose intolerance, but females did not. This was true even when males and females gained a similar amount of weight.

Searching the literature for something that could explain this, the team identified a transcription factor called BCL6, which prevents the breakdown of fat in the liver and is much more present in male mice.

Deleting the gene for this protein eliminated liver fat in the males, and also their ability to survive the infection.

“The host defence programs in the liver are the predisposing factors that drive fatty liver in males,” said Joni Nikkanen, PhD, a postdoctoral fellow and one of the study researchers.

“We have an evolutionary perspective on why such programs have developed — because they protect males against bacterial infections,” he said. “But in another context, these same programs are not good for you anymore, and you will develop more severe fatty liver.”

The team also examined how the presence of BCL6 affected gene expression in the liver. This process begins at puberty when males produce more testosterone, and their pituitary glands start to secrete growth hormone in sharp peaks and valleys.

These intermittent bursts, likely testosterone-regulated, are important. When researchers infused male mice continuously with growth hormone the way it is secreted in females, BCL6 disappeared from their livers, and they lost the ability to fight E. coli infection.

The results point to growth hormone as a potential therapy for adults with fatty liver disease, an idea that is currently being tested. Its effects are already well established in children whose pituitaries don’t produce enough growth hormone. Male children especially tend to develop fatty liver, but it goes away when they are given growth hormone to treat their short stature.

The work also expands the scientific view of how the body fights infection to include organs like the liver.

“The fight is still between the infection and the immune system,” said Omer Gokcumen, PhD, an evolutionary anthropologist at the University at Buffalo and a co-author of the study. “But the liver is determining the battlefield.”

Source: University of California – San Francisco

Categories : Diseases, Syndromes and ConditionsTags :

Kisspeptin Might Be a New Treatment for Fatty Liver Disease

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The Hershey’s Kisses after which the hormone is named. Photo by Aaron Burden on Unsplash

Kisspeptin, a hormone named for the iconic Hershey’s ‘Kisses’ might be developed as a treatment for non-alcoholic fatty liver disease (NAFLD), according to a new study appearing in the Journal of Clinical Investigation. The hormone also serves to regulate puberty and fertility in humans. 

Globally, non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease that affects children and adults and is linked to the rise in obesity and Type 2 diabetes. Largely without symptoms in the early stages, NAFLD begins with the accumulation of fat in the liver, leading to ‘fatty liver’. With disease progression, inflammation sets in, resulting in non-alcoholic steatohepatitis (NASH). This is followed by fibrosis and cirrhosis, and a subset of NASH patients with cirrhosis will also develop liver cancer. There are presently no approved therapeutics to treat NASH.

Study lead investigator, Moshmi Bhattacharya, an associate professor at Rutgers University, has spent over 15 years studying kisspeptin in health and disease. Kisspeptin, encoded by the KISS1 gene, was discovered in a city called Hershey, and named for the iconic Hershey chocolate ‘kisses’. As well as playing key roles in pubertal development and maintaining reproductive function, kisspeptin has also been linked to appetite and, coincidentally given its name, sexual attraction.

In the study, mice fed on a high-fat, high-sugar ‘Western’ diet to induce obesity and NAFLD, were protected from the development of fatty liver, NASH and fibrosis when given kisspeptin. Kisspeptin works by binding its receptor, a protein called KISS1R, which, when deleted from liver cells, prevents kisspeptin from functioning, leading mice on Western diets to develop fatty liver. These experiments uncover a powerful relationship between kisspeptin and the reduction of liver fat and fibrosis.
“This work shows the kisspeptin receptor signaling pathway has a potential therapeutic role in NAFLD,” said co-author, Professor Vinod K Rustgi. “It does this by protecting against the development of fat in the liver and reducing inflammation and fibrosis. As such, it has the potential to favorably impact the health and lives of millions of patients around the globe.”

Source: Rutgers University

Categories : Diseases, Syndromes and Conditions GenderTags :

Sex Differences in Nonalcoholic Fatty Liver Disease Explained

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Toilet sign male and female
Photo by Tim Mossholder on Unsplash

Investigators may have discovered the reason why fewer women than men develop nonalcoholic fatty liver disease (NAFLD). They published their findings in Nature Communications.

One of the most common disorders globally, NAFLD is a leading cause of death worldwide. Its progressive form, ‘nonalcoholic steatohepatitis’ (NASH), affects about 30% of all NAFLD patients, and can lead to cirrhosis and liver cancer. Despite intensive research, the underlying mechanisms of NAFLD/NASH are still poorly understood and effective treatment is lacking as a result.

However, it is known that NAFLD/NASH is more common among men than women, especially premenopausal women. The reasons for this are still unclear, but evidence so far suggests that oestrogen plays a protective role. On the other hand, the protein formyl peptide receptor 2 (FPR2) is known to play an important role in mediating inflammatory responses in multiple organs. However, no study so far has determined its role in the liver. Could FPR2 be involved in the sex-related differences regarding NAFLD prevalence and severity?

Addressing this question, a research team led by Professor Youngmi Jung of Pusan National University, Korea, recently conducted a study using mice model, shedding light on the role of FPR2 in NAFLD/NASH and its relationship to the observed sex-based differences. This work is among the very few studies on NAFLD that relies on sex-balanced animal experiments rather than the more common male-only designs.

The researchers first found that Fpr2 was highly expressed in healthy livers of female mice. Furthermore, it was expressed differently in the livers of male and female mice that were fed a special NAFLD-inducing diet. Silencing the Fpr2 gene made the male and female mice equally vulnerable to NAFLD, suggesting that FPR2 has a protective effect on the liver.

Interestingly, the researchers also found that FPR2 production in the liver is mediated by oestrogen. Males supplemented with external oestrogen produced more Fpr2 and were more resistant to NAFLD, whereas females that had their ovaries removed exhibited reduced liver Fpr2 levels. “Taken together, our findings suggest that FPR2 is a potential therapeutic target for developing pharmacological agents to treat NAFLD/NASH,” says Prof Jung. “In addition, our results could help in the development of gender-based therapies for NASH.”

This unprecedented discovery of the female-specific production of FPR2 in the liver and its role in providing resistance against NAFLD/NASH will hopefully pave the way not only for novel treatments but also a more comprehensive and sex-aware approach when doing science. Prof Jung remarked on this: “Our research highlights the pressing need for designing and developing better sex-balanced animal experiments, considering that the sex-specific expression of FPR2 in the liver had been completely overlooked in previous studies.”

Source: Pusan National University