Bile acids, a structurally related group of molecules derived from cholesterol, have a long history as therapeutic agents in medicine, from treatment for primarily ocular diseases in ancient Chinese medicine to modern day use as approved drugs for certain liver diseases. Despite evidence supporting a neuroprotective role in a diverse spectrum of age-related neurodegenerative disorders, including several small pilot clinical trials, little is known about their molecular mechanisms or their physiological roles in the nervous system. We review the data reported for their use as treatments for neurodegenerative diseases and their underlying molecular basis. While data from cellular and animal models and clinical trials support potential efficacy to treat a variety of neurodegenerative disorders, the relevant bile acids, their origin, and the precise molecular mechanism(s) by which they confer neuroprotection are not known delaying translation to the clinical setting.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent complication of extreme obesity. Loading of the liver with fat can progress to inflammation and fibrosis including cirrhosis. The molecular factors involved in the progression from simple steatosis to fibrosis remain poorly understood. Gene expression profiling using microarray, PCR array, and RNA sequencing was performed on RNA from liver biopsy tissue from patients with extreme obesity. Patients were grouped based on histological findings including normal liver histology with no steatosis, lobular inflammation, or fibrosis, and grades 1, 2, 3, and 4 fibrosis with coexistent steatosis and lobular inflammation. Validation of expression was conducted using quantitative PCR. Serum analysis was performed using ELISA. Expression analysis of hepatocytes and hepatic stellate cells in response to lipid loading were conducted in vitro using quantitative PCR and ELISA. Three orthogonal methods to profile human liver biopsy RNA each identified the chemokine CCL20 (CC chemokine ligand 20 or MIP-3 alpha) gene as one of the most up-regulated transcripts in NAFLD fibrosis relative to normal histology, validated in a replication group. CCL20 protein levels in serum measured in 224 NAFLD patients were increased in severe fibrosis (p < 0.001), with moderate correlation of hepatic transcript levels and serum levels. Expression of CCL20, but not its cognate receptor CC chemokine receptor 6, was significantly (p < 0.001) increased in response to fatty acid loading in LX-2 hepatic stellate cells, with relative increases greater than those in HepG2 hepatocyte cells. These results suggest that expression of CCL20, an important inflammatory mediator, is increased in NAFLD fibrosis. CCL20 serves as a chemoattractant molecule for immature dendritic cells, which have been shown to produce many of the inflammatory molecules that mediate liver fibrosis. These data also point to hepatic stellate cells as a key cell type that may respond to lipid loading of the liver.

Nonalcoholic fatty liver disease (NAFLD) can develop in lean individuals. Despite a better metabolic profile, the risk of disease progression to hepatic inflammation, fibrosis, and decompensated cirrhosis in the lean is similar to that in obesity-related NAFLD and lean individuals may experience more severe hepatic consequences and higher mortality relative to those with a higher body mass index (BMI). In the absence of early symptoms and abnormal laboratory findings, lean individuals are not likely to be screened for NAFLD or related comorbidities; however, given the progressive nature of the disease and the increased risk of morbidity and mortality, a clearer understanding of the natural history of NAFLD in lean individuals, as well as efforts to raise awareness of the potential health risks of NAFLD in lean individuals, are warranted. In this review, we summarize available data on NAFLD prevalence, clinical characteristics, outcomes, and mortality in lean individuals and discuss factors that may contribute to the development of NAFLD in this population, including links between dietary and genetic factors, menopausal status, and ethnicity. We also highlight the need for greater representation of lean individuals in NAFLD-related clinical trials, as well as more studies to better characterize lean NAFLD, develop improved screening algorithms, and determine specific treatment strategies based on underlying etiology.

Long noncoding RNAs (lncRNAs) are pervasively transcribed in the genome, exhibit a diverse range of biological functions, and exert effects through a variety of mechanisms. The sheer number of lncRNAs in the human genome has raised important questions about their potential biological significance and roles in human health and disease. Technological and computational advances have enabled functional annotation of a large number of lncRNAs. Though the number of publications related to lncRNAs has escalated in recent years, relatively few have focused on those involved in hepatic physiology and pathology. We provide an overview of evolving lncRNA classification systems and characteristics and highlight important advances in our understanding of the contribution of lncRNAs to liver disease, with a focus on nonalcoholic steatohepatitis, hepatocellular carcinoma, and cholestatic liver disease.

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of conditions that include steatohepatitis and fibrosis that are thought to emanate from hepatic steatosis. Few robust biomarkers or diagnostic tests have been developed for hepatic steatosis in the setting of obesity. We have developed a multi-component classifier for hepatic steatosis comprised of phenotypic, genomic, and proteomic variables using data from 576 adults with extreme obesity who underwent bariatric surgery and intra-operative liver biopsy. Using a 443 patient training set, protein biomarker discovery was performed using the highly multiplexed SOMAscan^® proteomic assay, a set of 19 clinical variables, and the steatosis predisposing PNPLA3 rs738409 single nucleotide polymorphism genotype status. The most stable markers were selected using a stability selection algorithm with a L₁-regularized logistic regression kernel and were then fitted with logistic regression models to classify steatosis, that were then tested against a 133 sample blinded verification set. The highest area under the ROC curve (AUC) for steatosis of PNPLA3 rs738409 genotype, 8 proteins, or 19 phenotypic variables was 0.913, whereas the final classifier that included variables from all three domains had an AUC of 0.935. These data indicate that multi-domain modeling has better predictive power than comprehensive analysis of variables from a single domain.

Choline deficiency causes hepatic fat accumulation, and is associated with a higher risk of nonalcoholic fatty liver disease (NAFLD) and more advanced NAFLD-related hepatic fibrosis. Reduced expression of hepatic phosphatidylethanolamine N-methyltransferase (PEMT), which catalyzes the production of phosphatidylcholine, causes steatosis, inflammation, and fibrosis in mice. In humans, common PEMT variants impair phosphatidylcholine synthesis, and are associated with NAFLD risk. We investigated hepatic PEMT expression in a large cohort of patients representing the spectrum of NAFLD, and examined the relationship between PEMT genetic variants and gene expression. Hepatic PEMT expression was reduced in NAFLD patients with inflammation and fibrosis (i.e., nonalcoholic steatohepatitis or NASH) compared to participants with normal liver histology (β = −1.497; p = 0.005). PEMT levels also declined with increasing severity of fibrosis with cirrhosis < incomplete cirrhosis < bridging fibrosis (β = −1.185; p = 0.011). Hepatic PEMT expression was reduced in postmenopausal women with NASH compared to those with normal liver histology (β = −3.698; p = 0.030). We detected a suggestive association between rs7946 and hepatic fibrosis (p = 0.083). Although none of the tested variants were associated with hepatic PEMT expression, computational fine mapping analysis indicated that rs4646385 may impact PEMT levels in the liver. Hepatic PEMT expression decreases with increasing severity of NAFLD in obese individuals and postmenopausal women, and may contribute to disease pathogenesis in a subset of NASH patients.