A Systematic Review of Animal Models of NAFLD Finds High-Fat, High-Fructose Diets Most Closely Resemble Human NAFLD.

BACKGROUND AND AIMS: Animal models of human disease are a key component of translational hepatology research, yet there is no consensus on which model is optimal for NAFLD. APPROACH AND RESULTS: We generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous, and therefore, few models had been cited more than once. Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high-fat, high-fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the field of hepatology and beyond. CONCLUSIONS: This systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication.

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.

BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8×10-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.

An AGTR1 Variant Worsens Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome.

Nonalcoholic fatty liver disease and hypertension are closely related but there has been little genetic evidence to link them. In this issue, Musso et al. provide evidence that a common variant in AGTR1 (A1166C) is associated with both incident hypertension and nonalcoholic fatty liver disease, as well as nonalcoholic steatohepatitis, fibrosis, dyslipidemia, and insulin resistance. AGTR1 is strongly expressed in adipose, liver, and arteries. The mechanism of this gain-of-function variant is unclear but may include adipose or endothelial dysfunction and immune activation. Despite previous unsuccessful clinical trials of angiotensin receptor blockers in nonalcoholic steatohepatitis, individuals with the rs5186A>C variant may have greater benefit from this therapy.

Weight loss, insulin resistance, and study design confound results in a meta-analysis of animal models of fatty liver.

The classical drug development pipeline necessitates studies using animal models of human disease to gauge future efficacy in humans, however there is a low conversion rate from success in animals to humans. Non-alcoholic fatty liver disease (NAFLD) is a complex chronic disease without any established therapies and a major field of animal research. We performed a meta-analysis with meta-regression of 603 interventional rodent studies (10,364 animals) in NAFLD to assess which variables influenced treatment response. Weight loss and alleviation of insulin resistance were consistently associated with improvement in NAFLD. Multiple drug classes that do not affect weight in humans caused weight loss in animals. Other study design variables, such as age of animals and dietary composition, influenced the magnitude of treatment effect. Publication bias may have increased effect estimates by 37-79%. These findings help to explain the challenge of reproducibility and translation within the field of metabolism.

Obesity and diabetes are increasingly common diseases that can lead to other complications such as fatty liver disease. Fatty liver disease affects one in five people and is caused by a built-up of fat in the liver, which can result in scarring of the liver tissue and other serious complications. There is currently no cure for fatty liver disease. Drugs that have been effective in treating the condition in mice, lack efficacy in humans. To better understand why this is the case, Hunter, de Gracia Hahn, Duret, Im et al. conducted a review of over 5,000 published studies, analysing over 600 experiments. Hunter et al. asked which drugs improved fatty liver in mice the most and if they had the same effect in humans. They also tested whether the age of the mice affected the outcome of the experiments. The analyses revealed that the drugs that work best in mice are different to the ones that show some effect in humans. In mice, many of the drugs reduced their weight or lowered their blood sugar levels, which also improved the fatty liver condition. Moreover, drugs appeared to be less effective the older the mice were. However, most of these drugs do not cause weight loss or lower blood sugar levels in humans, suggesting that factors other than the intended action of these drug could affect the outcome of a mouse study. These findings will help shape future research into obesity, diabetes and fatty liver disease using mice. They highlight that results obtained from studies with mice so far do not predict if a drug will work in humans to treat fatty liver disease. Moreover, weight loss seems to be the most important factor linked to how efficiently a drug treats fatty liver disease.

The infrared reflex: a potential new method for congenital cataract screening.

OBJECTIVE: To compare the accuracy of infrared (IR)-reflex assessment using a prototype imaging device to standard non-mydriatic red-reflex screening with direct ophthalmoscope (DO) in the diagnosis of neonatal and childhood cataract. METHODS: The comparison of the techniques was made in two distinct cohorts: in the first, newborns underwent IR and red-reflex testing by a medical student, with results compared to a reference red-reflex examination by an experienced midwife. In the second, an enriched cohort of children attending a specialist paediatric ophthalmology clinic had IR and red-reflex testing by a medical student to reference examination by a paediatric ophthalmologist. The medical students were considered inexperienced screeners due to their limited exposure to ophthalmology. The sensitivity and specificity of the IR and red-reflex assessments in respect to reference examination were calculated. Diagnostic accuracy was compared in Caucasian and non-Caucasian eyes. RESULTS: IR and red-reflex imaging were possible in all 180 neonatal eyes examined. A total of 5% of newborn eyes were found to have embryological remnants in the anterior segment of the eye with IR-reflex imaging which were not detected on reference red-reflex examination. IR-reflex assessment had significantly better sensitivity (100 vs 71%, p < 0.05) and specificity (100 vs 63%, p < 0.01) than red-reflex assessment in the diagnosis of childhood cataract. Red-reflex specificity was particularly poor in non-Caucasian eyes compared to Caucasian eyes (32 vs 72%, p < 0.05). CONCLUSION: This pilot study indicates that IR-reflex imaging has the potential to improve the diagnostic accuracy of eye screening for cataract by inexperienced healthcare staff, particularly in non-Caucasian children.