Shelly C Lu

Cedars-Sinai Medical Center · Department of Medicine

Methionine adenosyltransferase 2 A (MAT2A) and MAT2B are essential for hepatic stellate cells (HSCs) activation. Forkhead box M1 (FOXM1) transgenic mice develop liver inflammation and fibrosis. Here we examine if they crosstalk in male mice. We found FOXM1/MAT2A/2B are upregulated after bile duct ligation (BDL) and carbon tetrachloride (CCl4) treat...

Background Metabolic syndrome (MetS) is a cluster of medical conditions and risk factors correlating with insulin resistance that increase the risk of developing cardiometabolic health problems. The specific criteria for diagnosing MetS vary among different medical organizations but are typically based on the evaluation of abdominal obesity, high b...

Lipidomics has unveiled the intricate human lipidome, emphasizing the extensive diversity within lipid classes in mammalian tissues critical for cellular functions. This diversity poses a challenge in maintaining a delicate balance between adaptability to recurring physiological changes and overall stability. Metabolic Dysfunction-Associated Steato...

MCJ (Methylation-Controlled J protein), an endogenous repressor of the mitochondrial respiratory chain, is upregulated in multiple liver diseases but little is known about how it is regulated. S-adenosylmethionine (SAMe), the biological methyl donor, is frequently depleted in chronic liver diseases. Here, we show that SAMe negatively regulates MCJ...

Background & Aims Methionine adenosyltransferase alpha1 (MATα1) is responsible for the biosynthesis of S-adenosylmethionine (SAMe) in normal liver. Alcohol consumption enhances MATα1 interaction with peptidylprolyl cis-trans isomerase NIMA-interacting 1 (PIN1), which blocks MATα1 mitochondrial targeting, resulting in lower mitochondrial MATα1 conte...

Background: We established a novel diethylnitrosamine (DEN) -induced mouse model that reflected the progression of cholangiocarcinoma (CCA) from atypical cystic hyperplasia. Methods: BALB/c mice were administered DEN by oral gavage. Cells isolated from livers were analyzed for expression of CSNK2A1, MAX and MAX-interacting proteins. Human CCA ce...

Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (...

Methionine adenosyltransferase 1a (MAT1A) is responsible for hepatic S-adenosyl-L-methionine (SAMe) biosynthesis. Mat1a-/- mice have hepatic SAMe depletion, develop nonalcoholic steatohepatitis (NASH) which is reversed with SAMe administration. We examined temporal alterations in the proteome/phospho-proteome in pre-disease and NASH Mat1a-/- mice,...

With a better understanding of the pathophysiological and metabolic changes in hepatocellular carcinoma (HCC), multiparametric and novel functional magnetic resonance (MR) and positron emission tomography (PET) techniques have received wide interest and are increasingly being applied in preclinical and clinical research. These techniques not only a...

After SARS-CoV-2 infection, the molecular phenoreversion of the immunological response and its associated metabolic dysregulation are required for a full recovery of the patient. This process is patient-dependent due to the manifold possibilities induced by virus severity, its phylogenic evolution and the vaccination status of the population. We ha...

One carbon metabolism (1CM) can be defined as the transfer of a carbon unit from one metabolite to another and its replenishment by different sources of labile methyl-group nutrients: primarily choline, methionine, betaine, and serine. This flow of carbon units allows the biosynthesis of nucleotides, amino acids, formylated methionyl-tRNA, polyamin...

Adipose tissue dysfunction is closely associated with the development and progression of nonalcoholic fatty liver disease (NAFLD). Recent studies have implied an important role of prohibitin‐1 (PHB1) in adipose tissue function. In the current study, we aimed to explore the function of adipocyte PHB1 in the development and progression of NAFLD. The...

Fatty liver is a highly heterogenous condition driven by various pathogenic factors in addition to the severity of steatosis. Protein insufficiency has been causally linked to fatty liver with incompletely defined mechanisms. Here we report that fatty liver is a sulfur amino acid insufficient state that promotes metabolic inflexibility via limiting...

Background and aims: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. Approach and r...

Studies have examined nonalcoholic fatty liver disease (NAFLD) prevalence and severity in Asians; however, this is not well understood in Asian Americans (both East and South Asian Americans) as few studies have analyzed this population. We aimed to describe characteristics, prevalence of NAFLD, and its severity in Asian Americans in the National H...

Biliary cysts are distinct from polycystic liver disease (PLD), which is a condition characterized by the progressive development of >20 fluid‐filled cysts in the liver. This chapter reviews current understanding of cystic diseases of the biliary tract and PLD. Given the more nonspecific symptoms and broader differential diagnosis, choledochal cyst...

This chapter offers diverse images that provide an overview on the cystic diseases of the liver and biliary tract and aims to provide a synopsis through pictures and illustrations rather than through text. Clinical presentation of biliary cysts depends on the patient's age. Diagnosis of biliary cysts requires a high index of suspicion. Percutaneous...

Background & aims: We previously identified subsets of NAFLD patients with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. Approach & results: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impai...

MATα1 catalyzes the synthesis of S-adenosylmethionine, the principal biological methyl donor. Lower MATα1 activity and mitochondrial dysfunction occur in alcohol-associated liver disease. Besides cytosol and nucleus, MATα1 also targets the mitochondria of hepatocytes to regulate their function. Here, we show that mitochondrial MATα1 is selectively...

This study uses data from the Surveillance Epidemiology and End Results database to perform an age- and sex-specific time trend analysis of pancreatic cancer incidence rates in US adults.

Methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor downregulated in hepatocellular carcinoma and cholangiocarcinoma, two of the fastest rising cancers worldwide. We compared MATα1 (protein encoded by MAT1A) interactome in normal versus cancerous livers by mass spectrometry to reveal interactions with 14-3-3ζ. The MATα1/14-3-3ζ complex...

Background & aims: Methionine adenosyltransferase 1A (MAT1A) is responsible for S-adenosylmethionine (SAMe) biosynthesis in the liver. Mice lacking Mat1a have hepatic SAMe depletion, develop non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) spontaneously. Several kinases are activated in Mat1a knockout (KO) mice livers. Howev...

Background Metabolic syndrome (MetS) is a multimorbid long-term condition without consensual medical definition and a diagnostic based on compatible symptomatology. Here we have investigated the molecular signature of MetS in urine. Methods We used NMR-based metabolomics to investigate a European cohort including urine samples from 11,754 individu...

Alcohol-associated liver disease (ALD) is a global health issue and leads to progressive liver injury, comorbidities, and increased mortality. Human-relevant preclinical models of ALD are urgently needed. Here, we leverage a triculture human Liver-Chip with biomimetic hepatic sinusoids and bile canaliculi to model ALD employing human-relevant blood...

BACKGROUND. Metabolic syndrome (MetS) is a multimorbid long-term condition without consensual medical definition and a diagnostic based on compatible symptomatology. Here we have investigated the molecular signature of MetS in urine. METHODS. We used NMR-based metabolomics to investigate a European cohort including urine samples from 11,754 individ...

Background: Recent trends of hepatocellular carcinoma (HCC) mortality and outcome remain unknown in the United States (US). We investigated the recent trends of primary liver cancer (excluding intrahepatic cholangiocarcinoma) mortality and HCC stage, treatment, and overall survival (OS) in the US. Methods: US Cancer Mortality database was analyz...

Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sor...

Introduction: Small studies from outside of the USA suggest excellent outcomes after surgical resection for hepatocellular carcinoma (HCC) with vascular invasion. The study aims to (1) compare overall survival after surgical resection and systemic therapy among patients with HCC and vascular invasion and (2) determine factors associated with recei...

Background and Aims: Systemic therapy remains the recommended first-line treatment for hepatocellular carcinoma (HCC) with macrovascular invasion (MVI). Transarterial radioembolization (TARE) is a promising alternative treatment given superior quality of life. The aims of this study were to 1) characterize trends and correlates for TARE as first-li...

Background & aims: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with a disproportionate impact on racial/ethnic minority groups. However, state-level variation in racial/ethnic disparities and temporal trends of HCC incidence remain unknown. Therefore, we aimed to characterize: 1) state-level racial/ethnic di...

Background & Aims Mitochondria are the major organelles for the formation of reactive oxygen species (ROS) in the cell, and mitochondrial dysfunction has been described as a key factor in the pathogenesis of cholestatic liver disease. The methylation-controlled J-protein (MCJ) is a mitochondrial protein that interacts with and represses the functio...

Effective therapies for alcohol-associated liver disease (ALD) are limited; therefore, the discovery of new therapeutic agents is greatly warranted. Toll-like receptor 7 (TLR7) is a pattern recognition receptor for single-stranded RNA, and its activation prevents liver fibrosis. We examined liver and intestinal damage in Tlr7 -/- mice to determine...

Background and aims: The liver plays a central role in all metabolic processes in the body. However, precise characterization of liver metabolism is often obscured by its inherent complexity. Phosphorylated metabolites occupy a prominent position in all anabolic and catabolic pathways. Here, we develop a 31 P nuclear magnetic resonance (NMR)-based...

COVID-19 is a systemic infection that exerts significant impact on the metabolism. Yet, there is little information on how SARS-CoV-2 affects metabolism. Using NMR spectroscopy, we measured the metabolomic and lipidomic serum profile from 263 (training cohort) + 135 (validation cohort) symptomatic patients hospitalized after positive PCR testing fo...

Background: Changing opinions on the alcohol abstinence requirement have led to increased liver transplantation (LT) for alcoholic hepatitis (AH). We aimed to determine the trend in LT for AH in the United States and overall and graft survival rates. Methods: Adult liver-alone and liver-kidney registrations added to the Organ Procurement and Tra...

COVID-19 is a systemic infection that exerts significant impact on the metabolism. Yet, there is little information on how SARS-CoV-2 affects metabolism. Using NMR spectroscopy, we measured the metabolomic and lipidomic serum profile from 263 (training cohort) + 135 (validation cohort) symptomatic patients hospitalized after positive PCR testing fo...

Proteoforms containing post-translational modifications (PTMs) represent a degree of functional diversity only harnessed through analytically precise simultaneous quantification of multiple PTMs. Here we present a method to accurately differentiate an unmodified peptide from its PTM-containing counterpart through data-independent acquisition-mass s...

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and the second most common cause of cancer mortality worldwide [...].

Background: Arachidyl amido cholanoic acid (Aramchol) is a potent downregulator of hepatic stearoyl-CoA desaturase 1 (SCD1) protein expression that reduces liver triglycerides and fibrosis in animal models of steatohepatitis. In a phase IIb clinical trial in patients with nonalcoholic steatohepatitis (NASH), 52 wk of treatment with Aramchol reduce...

Background: It remains unknown to what extent hepatocellular carcinomas (HCCs) are detected very early (T1 stage; ie, unifocal <2 cm) in the United States. The aim of this study was to investigate the trends and factors associated with very early detection of HCC and resultant outcomes. Methods: Patients with HCC diagnosed from 2004 through 2014...

Background and Aims: For hepatocellular carcinoma (HCC) with vascular invasion, systemic treatment is recommended but transarterial radioembolization (TARE) is often used in clinical practice. The aim of this study was to investigate the current usage of TARE vs. systemic therapy as a first-line treatment for HCC with vascular invasion in the Unite...

Fatty liver disease (FLD), is a major public health burden that affects up to 30% of people in Western countries and leads to progressive liver injury, comorbidities, and increased mortality. Key risk factors for developing FLD are obesity and alcohol consumption, both of which are growing in prevalence worldwide. There is an urgent need for human-...

Glutathione (GSH), a tripeptide that is present in all mammalian tissues, is especially highly concentrated in the liver. GSH synthesis occurs via two adenosine triphosphate (ATP)-requiring enzymatic steps: the first is rate-limiting, catalyzed by glutamate-cysteine ligase, generates γ-glutamylcysteine from glutamate and cysteine; the second is cat...

Recent surges in mass spectrometry-based proteomics studies demands a concurrent rise in speedy and optimized data processing tools and pipelines. Although several stand-alone bioinformatics tools exist that provide protein-protein interaction (PPI) data, we developed Protein Interaction Network Extractor (PINE) as a fully automated, user-friendly,...

Patients with colorectal cancer (CRC) have benefited significantly from advances in multimodal treatment with significant improvements in long-term survival. More patients are currently being treated with surgical resection or ablation following neoadjuvant or adjuvant chemotherapy. However, several cytotoxic agents that are administered routinely...

Background Methionine adenosyltransferase alpha1 (MATα1) is responsible for hepatic biosynthesis of S‐adenosylmethionine (SAMe). Lower MATα1 activity and SAMe levels occur in alcoholic liver disease (ALD), a condition characterized by mitochondrial dysfunction. We recently showed MATα1 is in the mitochondrial matrix of hepatocytes and is important...

Background and aims: Forkhead box M1 (FOXM1) and nuclear factor kappa B (NF-ĸB) are oncogenic drivers in liver cancer that positively regulate each other. We showed that methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor in the liver and inhibits NF-ĸB activity. Here, we examined the interplay between FOXM1/NF-κB and MAT1A in liver ca...

Prohibitin 1 is an evolutionary conserved and ubiquitously expressed protein that exerts different biological functions depending on its subcellular localization. The role of prohibitin 1 in liver cancer is controversial as it can be pro- or anti-tumorigenic. However, most of the studies to date have described prohibitin 1 primarily as a tumor supp...

Hepatocellular carcinoma (HCC) is among the leading causes of worldwide cancer-related morbidity and mortality. Poor prognosis of HCC is mainly attributed to tumor presentation at an advanced stage when there is no effective treatment to achieve the long term survival of patients. Currently available tests such as alpha-fetoprotein (AFP) have limit...

Non-alcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatic fat in an inflammatory/fibrotic background. Herein, we show that the hepatic high-activity glutaminase 1 isoform (GLS1) is overexpressed in NASH. Importantly, GLS1 inhibition reduces lipid content in choline and/or methionine deprivation-induced steatotic mouse pri...

Proteoforms containing post-translational modifications (PTMs) represent a degree of functional diversity only harnessed through analytically precise simultaneous quantification of multiple PTMs. Here we present a method to accurately differentiate an unmodified peptide from its PTM-containing counterpart through data-independent acquisition-mass s...

Fatty liver disease (FLD), is a major public health burden that affects up to 30% of people in Western countries and leads to progressive liver injury, comorbidities, and increased mortality. Key risk factors for developing FLD are obesity and alcohol consumption, both of which are growing in prevalence worldwide. There is an urgent need for human-...

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide. Delayed diagnosis is a major factor responsible for the poor prognosis of HCC. Several advances have been made in the field of liver imaging with the use of novel imaging contrasts, improving current imaging techniques with contrast-enhanced computed tomogra...

Methionine adenosyltransferases (MATs) are essential enzymes for life as they produce S-adenosylmethionine (SAMe), the biological methyl donor required for a plethora of reactions within the cell. Mammalian systems express two genes, MAT1A and MAT2A, which encode for MATα1 and MATα2, the catalytic subunits of the MAT isoenzymes, respectively. A thi...

Objective: Non-alcoholic fatty liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolic pathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation and fibrosis. The enzyme glycine N-methyltransferase (GNMT), the most impo...

Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy. NAFLD covers a spectrum that ranges from simple steatosis, nonalcoholic steatohepatitis (NASH) with varying degrees of fibrosis, to cirrhosis, which is a major risk factor for hepatocellular carcinoma. Lifestyle and eating...

Hyaluronan (HA), a major extracellular matrix glycosaminoglycan, is a biomarker for cirrhosis. However, little is known about the regulatory and downstream mechanisms of HA overproduction in liver fibrosis. Hepatic HA and HA synthase 2 (HAS2) expression was elevated in both human and murine liver fibrosis. HA production and liver fibrosis were redu...

Aim: Methionine adenosyltransferase α1 (MATα1, encoded by MAT1A) is responsible for hepatic biosynthesis of S-adenosylmethionine, the principal methyl donor. MATα1 also act as a transcriptional co-factor by interacting and influencing the activity of several transcription factors. Mat1a knockout (KO) mice have increased levels of cytochrome P450 2...