Publications by authors named "Utpal Pajvani"
The peptide hormone kisspeptin attenuates liver steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and fibrosis in mouse models by signaling via the kisspeptin 1 receptor (KISS1R). However, whether kisspeptin impacts fibrogenesis in the human liver is not known. We investigated the impact of a potent kisspeptin analog (KPA) on fibrogenesis using human precision-cut liver slices (hPCLS) from fibrotic livers from male patients, in human hepatic stellate cells (HSCs), LX-2, and in primary mouse HSCs.
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- The study investigates the role of the KCTD17 protein in hepatocellular carcinoma (HCC) and its potential implications for treatment.
- KCTD17 was found to be upregulated in HCC tumors, and it promotes cancer cell proliferation and migration by stabilizing the Ras protein through a degradation mechanism involving the Cul3 ligase complex.
- Targeting KCTD17 with antisense oligonucleotides reduced tumor growth in mouse models, suggesting it could be a new therapeutic target for HCC.
Article Synopsis
- - Diabetes is a complex metabolic disorder that causes high blood sugar and can lead to serious complications, affecting overall health and increasing the risk of death.
- - Type 1 diabetes (T1D) is caused by the immune system destroying insulin-producing beta cells, while Type 2 diabetes (T2D) involves a combination of beta cell dysfunction and insulin resistance, often linked to obesity.
- - Understanding the genetic and environmental factors that contribute to diabetes may help improve treatment and management strategies, potentially changing its widespread impact.
Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice.
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- * The FDA recently conditionally approved resmetirom, a new drug targeting liver health, which has shown effectiveness in treating non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) by reducing liver fat and improving liver function without significant impact on body weight.
- * While resmetirom has a good safety profile with mostly mild side effects, challenges in patient selection and ongoing monitoring are needed for successful treatment, marking it as a significant advancement in addressing MASLD/MASH.
Article Synopsis
- * The mechanisms behind liver fibrosis are complex and mainly start in liver cells (hepatocytes), but are still not fully understood despite many studies.
- * A study in the JCI highlights a specific pathway (ATF3/HES1/CEBPA/OPN) that connects signals from hepatocytes to the activation of cells leading to fibrosis, suggesting potential new treatment strategies for liver fibrosis caused by MASLD.
Article Synopsis
- The study investigates the role of Jagged1, a ligand in the Notch signaling pathway, in β cell dysfunction associated with obesity and type 2 diabetes (T2D).
- Researchers used mouse models and human patient samples to analyze Notch pathway components and their effects on insulin secretion.
- Results indicate that blocking Jagged1 improves insulin secretion, highlighting its potential as a therapeutic target, although β cells themselves may not be the primary sources of the Jagged1 signal.
Tumorigenesis from non-alcoholic steatohepatitis to hepatocellular carcinoma.
Med Rev (2021)
December 2022
Article Synopsis
- Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of liver cancer, specifically hepatocellular carcinoma (HCC), especially in individuals with metabolic syndrome.
- The exact mechanisms behind how NASH leads to HCC are not fully understood, prompting further research into genetic alterations and the immune environment associated with this type of cancer.
- Recent studies suggest that NASH-related HCC may involve unique processes that require additional investigation to uncover their complexities.*
Article Synopsis
- Metabolic dysfunction-associated fatty liver disease (MAFLD) is strongly linked to insulin resistance, which is a key feature of type 2 diabetes, but the exact biological mechanisms connecting the two are not fully understood.
- The authors highlight that while insulin struggles to reduce glucose production in the liver, it still effectively stimulates the production of triglycerides (TG), leading to a condition called 'selective insulin resistance.'
- They suggest that the processes responsible for accumulating triglycerides in the liver require less insulin signaling than those controlling glucose production, explaining why elevated insulin levels can still lead to excessive liver fat despite impaired insulin action.
Article Synopsis
- Obesity is linked to chronic inflammation driven by macrophages infiltrating fat tissue, and the anti-inflammatory role of the protein PPARγ in these cells is not fully understood.
- A study used a genetically modified mouse model that mimics acetylation of PPARγ specifically in macrophages to explore its impact on metabolic dysfunction and inflammation.
- The findings show that PPARγ acetylation increases pro-inflammatory macrophage activity in certain fat tissues, resulting in reduced energy expenditure and metabolic health, suggesting new avenues for potential treatments targeting these molecular changes.
Integrating stress signals-XBP1 as a novel mediator of intercellular crosstalk in non-alcoholic steatohepatitis.
Transl Gastroenterol Hepatol
September 2022
Calorie restriction increases lifespan. While some tissue-specific protective effects of calorie restriction have been described, the impact of calorie restriction on the gastrointestinal tract remains unclear. We found increased abundance of chromogranin A+, including orexigenic ghrelin+, endocrine cells in the stomach of calorie-restricted mice.
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- * Genetic experiments using Ccl2-knockout mice demonstrated that reducing hepatocyte-derived MCP-1 decreased liver macrophage infiltration and fibrosis, while forcing MCP-1 expression had the opposite effect.
- * The study further revealed that Notch signaling in hepatocytes drives MCP-1 expression, linking increased Notch activation to enhanced liver inflammation and fibrosis in NASH.
Article Synopsis
- Obesity leads to type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD), with increased levels of a protein called Kctd17 in the livers of obese individuals being linked to these conditions.
- In experiments with genetically modified mice and CRISPR technology, researchers found that elevated Kctd17 levels worsen glucose and lipid metabolism, while reducing Kctd17 improved these metabolic functions.
- The study suggests that Kctd17 promotes metabolic disturbances by stabilizing another protein called Chrebp, indicating that targeting Kctd17 could be a potential new treatment for obesity-related metabolic diseases.
Systemic glucose metabolism and insulin activity oscillate in response to diurnal rhythms and nutrient availability with the necessary involvement of adipose tissue to maintain metabolic homeostasis. However, the adipose-intrinsic regulatory mechanism remains elusive. Here, the dynamics of PPARγ acetylation in adipose tissue are shown to orchestrate metabolic oscillation in daily rhythms.
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- Hepatocellular carcinoma (HCC) is a major cause of cancer deaths, primarily occurring in patients with chronic liver disease and advanced fibrosis, with hepatic stellate cells (HSCs) playing a significant role.
- Research on mouse models showed that HSCs have a tumor-promoting function, interacting with liver cells to influence both liver cell (hepatocyte) growth and death during HCC development.
- A shift in HSC types during liver disease progression leads to increased HCC risk, where protective mediators become less active while tumor-promoting factors gain dominance.
Article Synopsis
- * Researchers observed a significant increase in β-cell mass in a mouse model of obesity caused by excessive calorie intake, identifying Sin3a as a key regulator in this process through RNA sequencing.
- * Mice lacking Sin3a specifically in their β-cells developed severe diabetes, indicating that Sin3a is crucial for developing β-cell mass after birth and opening up new avenues for understanding β-cell adaptation mechanisms.
Article Synopsis
- - β-cells in the pancreas are crucial for insulin production and maintaining stable blood sugar levels, and their function is influenced by various transcription factors, particularly MafA.
- - In type 2 diabetes, MafA expression decreases, leading to β-cell dysfunction and worsening disease, making it an important focus for research.
- - The article discusses how understanding the complex regulation of MafA, including its transcriptional and post-translational factors, could reveal new therapeutic strategies to improve β-cell health.
Article Synopsis
- The study examines how altered islet structure is linked to β cell dysfunction and the progression of type 2 diabetes (T2D), particularly focusing on the role of Notch signaling in this process.* ! -
- Researchers created mice that had increased Notch activity in β cells to investigate its effects, finding that this activation impaired insulin secretion and caused lasting glucose intolerance, even after stopping Notch activation.* ! -
- The findings suggest that Notch and Ephrin signaling pathways can permanently change islet architecture early in life, contributing to the issues seen in β cells in individuals with T2D.* !
Article Synopsis
- * The study reveals that the protein TOX4, which is influenced by cAMP and dexamethasone, plays a significant role in regulating HGP independently of insulin signaling.
- * Inhibition of TOX4 leads to reduced glucose production and improved glucose tolerance, suggesting it could be an important target for addressing diabetes-related metabolic issues.
Article Synopsis
- * Studies using various gene-targeting methods showed that silencing TAZ in liver cells of NASH-afflicted mice reduces HCC tumor growth by impacting oxidative DNA damage pathways.
- * The findings suggest that targeting TAZ and its associated oxidative stress mechanisms could offer new therapeutic strategies for managing NASH and preventing HCC development.
Article Synopsis
- Non-alcoholic fatty liver disease (NAFLD) ranges from simple fat buildup (steatosis) to more severe liver inflammation and injury (NASH), which can lead to fibrosis.
- Research indicates that the location of liver damage (periportal vs. pericentral) influences metabolic outcomes and fibrosis severity, suggesting that the disease's zonal differences affect how it presents clinically.
- Recent clinical trials show that treatments like cysteamine and obeticholic acid may work better for specific types of liver damage, and pathways involved in liver development (like WNT/β-Catenin and Hedgehog) are important in understanding these zonal responses and individual patient differences in NASH.
Article Synopsis
- Aberrant activity of Notch signaling in liver cells is linked to the progression of NASH and liver fibrosis, with increased Jagged1 expression correlating with liver disease severity in both human and mouse models.* -
- This increase is caused by TLR4-NF-κB signaling in specific liver cells, which when manipulated can either worsen or protect against liver fibrosis based on the presence or absence of Jagged1.* -
- Investigating the potential for treatment, researchers developed targeted therapies that effectively reduced liver fibrosis in mice, highlighting Jagged1 as a promising target for NASH treatment in humans.*