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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.

Bile acids have recently emerged as potential neuroprotective agents that may modulate neurodegeneration. Most studies have focused on the single bile acid tauroursodeoxycholic acid (TUDCA) and its role as an anti-apoptotic agent. We studied other bile acids as signaling molecules for their two cellular receptors, farnesoid X receptor (FXR or NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), and for liver X receptor (LXR), as potential neurotrophic agents. We used two in vitro model systems to identify the effects of bile acids and related pharmacological agents on neurite outgrowth using quantitative image analysis. We also identified early effects on gene expression using RNA sequencing analysis. We found that 20 uM deoxycholic acid (DCA) could induce neurite outgrowth in NSC-34 cells that was comparable to the neurotrophic effects of the culture control 1 uM retinoic acid (RA) with similar, but slightly less robust effects observed for chenodexoycholic acid (CDCA) at 20 uM and in SH-SY5Y cells. Using chemical agonists and antagonists of FXR, LXR, and TGR5, TGR5 agonism was comparable to DCA stimulation, stronger than RA, and neither FXR nor LXR inhibition could block bile acid-induced neurite growth. RNA sequencing identified a core set of genes whose expression was regulated by DCA, CDCA, and RA. Our data suggest that bile acid signaling through TGR5 may be a targetable pathway to stimulate neurite outgrowth.

As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants’ health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.