Metabolic Dysfunction Associated with Steatohepatitis: A Review

WRITTEN BY JUNE MAJER

ILLUSTRATED BY ANDREA ARMENDI

February 2, 2025 | | 6 min read
The second leading cause for a liver transplant in the United States is metabolic dysfunction associated with steatohepatitis (MASH) in the liver, renamed from non-alcoholic steatohepatitis (NASH) in 2020, a known precursor to a cancer of the liver called hepatocellular carcinoma (HCC). Furthermore, MASH predicted to be the leading cause of liver transplant by 2030, although it can be reversed by improving liver health.1  Because a majority of the body’s metabolic functions are dependent upon the liver, where blood glucose levels, fatty acids and amino acid synthesis are all regulated, liver health deterioration affects the rest of the body in major ways. 

Liver health proceeds from (1) healthy liver, (2) hepatitis, inflammation of the liver, (3) fibrosis, scarring of the liver, and (4) cirrhosis, extreme scarring and permanent damage of the liver.2 Until the liver has reached cirrhosis, the liver can still regress back to the healthy stage. In the case of obesity and liver cancer, MASH is a critical stage of intervention before the health declines beyond reversibility. Despite the seriousness of MASH, current treatment recommendations mainly involve losing weight and changing one’s lifestyle. This could be attributed to the lack of knowledge on liver deterioration as well as the absence of FDA-approved drugs to treat MASH at any stage of liver health.3-4 However, researchers have found a strong correlation between the development of MASH and obesity. As a result, current MASH studies aim to determine best treatment approaches, including studies on the microbiota of the liver as well as regulation of genetic pathways expressed in MASH. 

In “Paneth Cell: The Missing Link between Obesity, MASH and Portal Hypertension,” Kumar et al studies the correlation between Paneth cells and MASH. Paneth cells are intestinal cells that produce antimicrobial peptides and proteins in defense of the host, and are postulated to be relevant to the mechanisms of hypertension and obesity. In another study, Ganguly et al. investigates the signaling pathways that are regulated within the cell relative to the progression of MASH. This led to their investigation of cross-talk of these pathways, or how a stimulator can elicit more than one pathway response. Meanwhile, Goh et al focuses on detecting MASH in patients by studying the possible mechanisms of MASH within the body.

The main strategy employed to track the progression of MASH as well as various activities and expressions in liver cells have been mice models, which relies on the shared  transcriptome between humans and mice.3  In Ganguly et al, the liver and serum of mice were collected to be studied using histology, H&E staining, sirius red, immunoblot analysis, and qRT-PCR. Mice Paneth cells were also examined to study the micro-bacteria in the gut in Kumar’s study. 

Detection of MASH in humans is currently confirmed by biopsy. Since this is a rather invasive method, Goh et al. studied how to detect the presence of MASH through serum levels and found an accuracy of 85% in ruling out MASH using the lower cutoff and and 91% in ruling in MASH using the upper cutoff.5 However, their study could not confidently diagnose fibrosis caused by non-alcoholic fatty liver disease (NAFLD) from ferritin levels in the blood alone.⁵ As a result, identifying MASH in check-up screenings remains a challenge. 

Similar to Goh et al.’s goal to create a predictive model of MASH in humans, Ganguly’s goal was to study the cross-talk and kinetics of liver cells as MASH progressed to HCC or vice versa.3  The model was based on mice overfed on a Western diet with high fat and high calories, which mimics the condition of MASH-developing humans with a high BMI/obesity.² Kumar found that one sign of liver degradation is a lack of the TGR5 bile receptor on the cell surface that promotes inflammation of the liver.4 TGR5 inhibits cytokines to prevent liver damage as part of an anti-inflammatory response.4 Without TGR5 receptors, a weaker anti-inflammatory response is initiated, and the liver experiences greater inflammation that progresses a healthy liver to hepatitis. In addition, less bile acid signaling leads to less fat breakdown in the liver, resulting in the accumulation of fat. This supports the trend of obesity developing alongside MASH.

Furthermore, Ganguly et al. noted that a high fat diet negatively impacts the digestive system. MASH was induced in mice through a mutation in the Alms gene to promote obesity from an increased appetite. They found that gut barrier dysfunction and dysbiosis develop in the early stages of liver deterioration.³ Dysbiosis refers to the irregular state of gut bacteria, leading to increased permeability of the gut. A possible explanation proposed by Kumar is that this is a symptom of Paneth cell dysfunction induced by a high fat diet, eventually leading to dysfunction of the gut barrier.4 Kumar outlines the effect of Paneth cell dysfunction in obese mouse models on both the digestive and hepatic systems: dysbiosis leads to a leaky gut, while MASH’s systemic inflammation and decreased anti-inflammatory response progresses the scarring of the liver from fibrosis to cirrhosis.

Ganguly et al. concluded that dysbiosis, inflammation, and leakiness in the gut are early occurrences in their mice model that will eventually develop into MASH and fibrosis.³ Kumar suggested that this is caused by an increased nutrient intake coupled with the accumulation of fats that stimulate ER stress while Paneth cells remain constant.4 In other words, despite increased stress on the organs, there is no increase of Paneth cells to manage the issue, resulting in dysbiosis of the gut. Furthermore, lipid metabolism and regulation takes place in the ER.6 Increased ER stress further down-regulates the metabolism of lipids, forcing it to accumulate in the liver.

In order to study the effects of time of intervention on liver health, the Ganguly et al. mice model stabilized the weight of their mice by switching the diets of MASH-developed mice from Western Diet to normal chow.³ This echoes current treatment plans that recommend a diet change to reverse the development of MASH. Similarly, in Czarnecka et al.’s study, they followed patients with underlying MASH who underwent a liver transplant and saw that the patients’ weight stabilized after three years.² This indicates that the plateauing weight of a patient is not the cause of MASH regression, but a symptom. 

Another worthwhile note is the cases of MASH examined by these papers do not result from alcohol consumption.  In the Ganguly et al. study, the mice model developed non-alcohol induced MASH. However, the Kumar study indicates that the presence of alcohol in the gut in patients with MASH causes stomach microbacteria to produce ethanol at a concentration high enough to be detected in the blood.4 This further accelerates steatosis, since the metabolism of the ethanol increases the presence of triglycerides in the gut from dysbiosis.4 

Studying the development of MASH is a key component of liver research. However,  the exact mechanisms of its progression are still unknown and remain relevant to current MASH studies. As research into MASH continues, future clinical trials and treatment plans may be implemented to ensure longevity and well-being of MASH patients. 

Acknowledgments

June Majer was an undergraduate volunteer in the Dhar lab under the UCSD Department of Medicine, which contributed to the Ganguly study.

References
  1. Czarnecka, K.; Czarnecka, P.; Tronina, O.; Bączkowska, T.; Durlik, M. MASH Continues as a Significant Burden on Metabolic Health of Liver Recipients. Transplantation proceedings 2024. https://doi.org/10.1016/j.transproceed.2024.02.007.
  2. How Liver Diseases Progress. American Liver Foundation. https://liverfoundation.org/about-your-liver/how-liver-diseases-progress/.
  3. Ganguly, S.; Muench, G. A.; Shang, L.; Rosenthal, S. B.; Rahman, G.; Wang, R.; Wang, Y.; Kwon, H. C.; Diomino, A. M.; Kisseleva, T.; Soorosh, P.; Hosseini, M.; Knight, R.; Schnabl, B.; Brenner, D. A.; Dhar, D. Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet. Cellular and molecular gastroenterology and hepatology 2021, 12 (3), 891–920. https://doi.org/10.1016/j.jcmgh.2021.05.010
  4. Kumar, M. S. Paneth Cell: The Missing Link between Obesity, MASH and Portal Hypertension. Clinics and research in hepatology and gastroenterology 2024, 48 (1), 102259–102259. https://doi.org/10.1016/j.clinre.2023.102259.
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  6. Liu, X.; Green, R. M. Endoplasmic Reticulum Stress and Liver Diseases. Liver Research 2019, 3 (1), 55–64. https://doi.org/10.1016/j.livres.2019.01.002.