Non-alcoholic Fatty Liver Disease Phenotype Research Articles

XBP1 links the 12-hour clock to NAFLD and regulation of membrane fluidity and lipid homeostasis

A distinct 12-hour clock exists in addition to the 24-hour circadian clock to coordinate metabolic and stress rhythms. Here, we show that liver-specific ablation of X-box binding protein 1 (XBP1) disrupts the hepatic 12-hour clock and promotes spontaneous non-alcoholic fatty liver disease (NAFLD). We show that hepatic XBP1 predominantly regulates the 12-hour rhythmicity of gene transcription in the mouse liver and demonstrate that perturbation of the 12-hour clock, but not the core circadian clock, is associated with the onset and progression of this NAFLD phenotype. Mechanistically, we provide evidence that the spliced form of XBP1 (XBP1s) binds to the hepatic 12-hour cistrome to directly regulate the 12-hour clock, with a periodicity paralleling the harmonic activation of the 12-hour oscillatory transcription of many rate-limiting metabolic genes known to have perturbations in human metabolic disease. Functionally, we show that Xbp1 ablation significantly reduces cellular membrane fluidity and impairs lipid homeostasis via rate-limiting metabolic processes in fatty acid monounsaturated and phospholipid remodeling pathways. These findings reveal that genetic disruption of the hepatic 12-hour clock links to the onset and progression of NAFLD development via transcriptional regulator XBP1, and demonstrate a role for XBP1 and the 12-hour clock in the modulation of phospholipid composition and the maintenance of lipid homeostasis.

Adverse muscle composition is linked to poor functional performance and metabolic comorbidities in NAFLD

Background & AimsSarcopenia and frailty are recognised as important factors in later stages of liver disease. However, their role in non-alcoholic fatty liver disease (NAFLD) is not yet fully understood. In this study we investigate the associations of MRI-measured adverse muscle composition (AMC: low muscle volume and high muscle fat) with poor function, sarcopenia, and metabolic comorbidity within NAFLD in the large UK Biobank imaging study.MethodsA total of 9,545 participants were included. Liver fat, fat-tissue free muscle volume, and muscle fat infiltration were quantified using a rapid MRI protocol and automated image analysis (AMRA® Researcher). For each participant, a personalised muscle volume z-score (sex- and body size-specific) was calculated and combined with muscle fat infiltration for AMC detection. The following outcomes were investigated: functional performance (hand grip strength, walking pace, stair climbing, falls) and metabolic comorbidities (coronary heart disease, type 2 diabetes). Sarcopenia was detected by combining MRI thresholds for low muscle quantity and low hand grip strength according to the European working group definition.ResultsThe prevalence of sarcopenia in NAFLD (1.6%) was significantly lower (p <0.05) compared with controls without fatty liver (3.4%), whereas the prevalence of poor function and metabolic comorbidity was similar or higher. Of the 1,204 participants with NAFLD, 169 (14%) had AMC and showed 1.7–2.4× higher prevalence of poor function (all p <0.05) as well as 2.1× and 3.3× higher prevalence of type 2 diabetes and coronary heart disease (p <0.001), respectively, compared with those without AMC.ConclusionsAMC is a prevalent and highly vulnerable NAFLD phenotype displaying poor function and high prevalence of metabolic comorbidity. Sarcopenia guidelines can be strengthened by including cut-offs for muscle fat, enabling AMC detection.Lay summaryToday, it is hard to predict whether a patient with fatty liver disease will progress to more severe liver disease. This study shows that measuring muscle health (the patient's muscle volume and how much fat they have in their muscles) could help identify the more vulnerable patients and enable early prevention of severe liver disease.

The transcontinental variability of nonalcoholic fatty liver disease.

To compare the phenotype of lean versus overweight (OW) and obese (OB) subjects with non-alcoholic fatty liver disease (NAFLD) across multiple continents. A retrospective study of histologically defined subjects from a single center each in France (Fr), Brazil (Br), India (In) and United States (US) was performed. A total of 70 lean [body mass index (BMI) < 25 kg/m2] subjects (Fr:Br:In:US: 16:19:22:13) with NAFLD were compared to 136 OW (BMI > 25 kg/m2, BMI < 29 kg/m2) (n = 28:33:52:23) and 224 OB subjects (BMI > 29 kg/m2) (n = 81:11:22:103). Lean French subjects had the lowest incidence of type 2 diabetes while those from Brazil (P < 0.01) had the highest. Lean subjects had similar low-density lipoprotein-cholesterol, but higher high-density lipoprotein-cholesterol compared to obese subjects in all regions. In both lean and obese subjects, there were both insulin-sensitive and insulin-resistant subjects. Lean French subjects were most insulin-sensitive while those from Brazil were mostly insulin-resistant. For each weight category, subjects from India were more insulin-sensitive than those from other regions. Disease activity increased from lean to overweight to obese in France but was similar across weight categories in other regions. The phenotype of NAFLD in lean subjects varies by region. Some obese subjects with NAFLD are insulin-sensitive. We hypothesize that genetics and region-specific disease modifiers account for these differences.

Adoptive transfer of Pfkfb3-disrupted hematopoietic cells to wild-type mice exacerbates diet-induced hepatic steatosis and inflammation

Background and objectivesHepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease (NAFLD). However, whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated. Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3/iPfk2) dissociates fat deposition and inflammation, the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice. MethodsPfkfb3-disrupted (Pfkfb3+/−) mice and wild-type (WT) littermates were fed a high-fat diet (HFD) and examined for NAFLD phenotype. Also, bone marrow cells isolated from Pfkfb3+/− mice and WT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation (BMT) to generate chimeric (WT/BMT- Pfkfb3+/−) mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric (WT/BMT-WT) mice. The latter were also fed an HFD and examined for NAFLD phenotype. In vitro, hepatocytes were co-cultured with bone marrow-derived macrophages and examined for hepatocyte fat deposition and proinflammatory responses. ResultsAfter the feeding period, HFD-fed Pfkfb3+/− mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice. When inflammatory activation was analyzed, Pfkfb3+/− macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation. When NAFLD phenotype was analyzed in the chimeric mice, WT/BMT-Pfkfb3+/− mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice. At the cellular level, hepatocytes co-cultured with Pfkfb3+/− macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages. ConclusionsPfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis. As such, the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.

Developmental Programming of NAFLD by Parental Obesity.

The surge of obesity across generations has become an increasingly relevant issue, with consequences for associated comorbidities in offspring. Data from longitudinal birth cohort studies support an association between maternal obesity and offspring nonalcoholic fatty liver disease (NAFLD), suggesting that perinatal obesity or obesogenic diet exposure reprograms offspring liver and increases NAFLD susceptibility. In preclinical models, offspring exposed to maternal obesogenic diet have increased hepatic steatosis after diet-induced obesity; however, the implications for later NAFLD development and progression are still unclear. Although some models show increased NAFLD incidence and progression in offspring, development of nonalcoholic steatohepatitis with fibrosis may be model dependent. Multigenerational programming of NAFLD phenotypes occurs after maternal obesogenic diet exposure; however, the mechanisms for such programming remain poorly understood. Likewise, emerging data on the role of paternal obesity in offspring NAFLD development reveal incomplete mechanisms. This review will explore the impact of parental obesity and obesogenic diet exposure on offspring NAFLD and areas for further investigation, including the impact of parental diet on disease progression, and consider potential interventions in preclinical models.

THU026 - Non-alcoholic fatty liver disease phenotype and prevalence across the menopause spectrum in women living with HIV

THU026 - Non-alcoholic fatty liver disease phenotype and prevalence across the menopause spectrum in women living with HIV

Early microcystin-LR exposure-linked inflammasome activation in mice causes development of fatty liver disease and insulin resistance

Evidence from pediatric studies show that infants and children are at risk for early exposure to microcystin. The present report tests the hypothesis that early life exposure to microcystin (MC), a principal component of harmful algal blooms followed by a juvenile exposure to high-fat diet feeding potentiate the development of nonalcoholic fatty liver disease phenotype in adulthood. Results showed classical symptoms of early NAFLD linked inflammation. Cytokines and chemokines such as CD68, IL-1β, MCP-1, and TNF-α, as well as α-SMA were increased in the groups that were exposed to MC-LR with the high-fat diet compared to the vehicle group. Also, mechanistically, NLRP3 KO mice showed a significant decrease in the inflammation and NAFLD phenotype and resisted the metabolic changes such as insulin resistance and glucose metabolism in the liver. The data suggested that MC-LR exposure and subsequent NLRP3 inflammasome activation in childhood could impact liver health in juveniles.

Indole Alleviates Diet-Induced Hepatic Steatosis and Inflammation in a Manner Involving Myeloid Cell 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3.

Indole is a microbiota metabolite that exerts anti-inflammatory responses. However, the relevance of indole to human non-alcoholic fatty liver disease (NAFLD) is not clear. It also remains largely unknown whether and how indole acts to protect against NAFLD. The present study sought to examine the association between the circulating levels of indole and liver fat content in human subjects and explore the mechanisms underlying indole actions in mice with diet-induced NAFLD. In a cohort of 137 subjects, the circulating levels of indole were reversely correlated with body mass index. In addition, the circulating levels of indole in obese subjects were significantly lower than those in lean subjects and were accompanied with increased liver fat content. At the whole-animal level, treatment of high-fat diet (HFD)-fed C57BL/6J mice with indole caused significant decreases in the severity of hepatic steatosis and inflammation. In cultured cells, indole treatment stimulated the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a master regulatory gene of glycolysis, and suppressed macrophage proinflammatory activation in a PFKFB3-dependent manner. Moreover, myeloid cell-specific PFKFB3 disruption exacerbated the severity of HFD-induced hepatic steatosis and inflammation and blunted the effect of indole on alleviating diet-induced NAFLD phenotype. Taken together, our results demonstrate that indole is relevant to human NAFLD and capable of alleviating diet-induced NAFLD phenotypes in mice in a myeloid cell PFKFB3-dependent manner. Therefore, indole mimetic and/or macrophage-specific PFKFB3 activation may be the viable preventive and/or therapeutic approaches for inflammation-associated diseases including NAFLD.

Mtrr hypomorphic mutation alters liver morphology, metabolism and fuel storage in mice

Nonalcoholic fatty liver disease (NAFLD) is associated with dietary folate deficiency and mutations in genes required for one‑carbon metabolism. However, the mechanism through which this occurs is unclear. To improve our understanding of this link, we investigated liver morphology, metabolism and fuel storage in adult mice with a hypomorphic mutation in the gene methionine synthase reductase (Mtrrgt). MTRR enzyme is a key regulator of the methionine and folate cycles. The Mtrrgt mutation in mice was previously shown to disrupt one‑carbon metabolism and cause a wide-spectrum of developmental phenotypes and late adult-onset macrocytic anaemia. Here, we showed that livers of Mtrrgt/gt female mice were enlarged compared to control C57Bl/6J livers. Histological analysis of these livers revealed eosinophilic hepatocytes with decreased glycogen content, which was associated with down-regulation of genes involved in glycogen synthesis (e.g., Ugp2 and Gsk3a genes). While female Mtrrgt/gt livers showed evidence of reduced β-oxidation of fatty acids, there were no other associated changes in the lipidome in female or male Mtrrgt/gt livers compared with controls. Defects in glycogen storage and lipid metabolism often associate with disruption of mitochondrial electron transfer system activity. However, defects in mitochondrial function were not detected in Mtrrgt/gt livers as determined by high-resolution respirometry analysis. Overall, we demonstrated that adult Mtrrgt/gt female mice showed abnormal liver morphology that differed from the NAFLD phenotype and that was accompanied by subtle changes in their hepatic metabolism and fuel storage.

The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus.

Diabetes mellitus is a metabolic disorder approaching epidemic proportions. Non-alcoholic fatty liver disease (NAFLD) regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. Recently, we demonstrated that the voltage-dependent anion channel 1 (VDAC1) is involved in NAFLD. VDAC1 is an outer mitochondria membrane protein that serves as a mitochondrial gatekeeper, controlling metabolic and energy homeostasis, as well as crosstalk between the mitochondria and the rest of the cell. It is also involved in mitochondria-mediated apoptosis. Here, we demonstrate that the VDAC1-based peptide, R-Tf-D-LP4, affects several parameters of a NAFLD mouse model in which administration of streptozotocin (STZ) and high-fat diet 32 (STZ/HFD-32) led to both type 2 diabetes (T2D) and NAFLD phenotypes. We focused on diabetes, showing that R-Tf-D-LP4 peptide treatment of STZ/HFD-32 fed mice restored the elevated blood glucose back to close to normal levels, and increased the number and average size of islets and their insulin content as compared to untreated controls. Similar results were obtained when staining the islets for glucose transporter type 2. In addition, the R-Tf-D-LP4 peptide decreased the elevated glucose levels in a mouse displaying obese, diabetic, and metabolic symptoms due to a mutation in the obese (ob) gene. To explore the cause of the peptide-induced improvement in the endocrine pancreas phenotype, we analyzed the expression levels of the proliferation marker, Ki-67, and found it to be increased in the islets of STZ/HFD-32 fed mice treated with the R-Tf-D-LP4 peptide. Moreover, peptide treatment of STZ/HFD-32 fed mice caused an increase in the expression of β-cell maturation and differentiation PDX1 transcription factor that enhances the expression of the insulin-encoding gene, and is essential for islet development, function, proliferation, and maintenance of glucose homeostasis in the pancreas. This increase occurred mainly in the β-cells, suggesting that the source of their increased number after R-Tf-D-LP4 peptide treatment was most likely due to β-cell proliferation. These results suggest that the VDAC1-based R-Tf-D-LP4 peptide has potential as a treatment for diabetes.

Evolution of NAFLD and Its Management.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be 25% and continues to rise worldwide in the setting of the obesity epidemic. This increase is especially concerning because NAFLD is often a progressive disease that can be associated with significant complications such as liver cirrhosis, hepatocellular carcinoma, and an increase in liver-related and overall mortality. Because of the devastating complications and comorbidities, NAFLD is a very costly disease for the healthcare system, with estimated annual direct medical costs exceeding $100 billion in the United States alone. Given this progressive course, it is imperative to make the diagnosis in patients with risk factors (metabolic syndrome, weight gain, and insulin resistance/diabetes). Once the diagnosis is made, the focus should shift to treatment and monitoring for the development of associated complications. Given that currently no pharmaceutical intervention is approved for the treatment of NAFLD, focus shifts instead to mitigation of risk factors through avoidance of foods that are rich in red meat, trans fats, refined carbohydrates, and high-fructose corn syrup; are low fiber; and have high energy density. The landmark of treatment, however, continues to be weight loss and improvement of insulin resistance, often through a multimodality approach. The current manuscript reviews the clinical phenotypes of NAFLD, its risk factors, and pathogenesis, as well as treatment options including lifestyle modifications and dietary interventions, medical therapies, endoscopic bariatric interventions, and bariatric surgery.

Lotus Seedpod Extracts Reduced Lipid Accumulation and Lipotoxicity in Hepatocytes.

Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic disorders, including hepatic lipid accumulation and lipotoxicity. Plant-derived polyphenols have attracted considerable attention in the prevention of NAFLD. Lotus seedpod, rich in polyphenols, is a traditional Chinese herbal medicine. Previous studies have showed that lotus seedpod possess radioprotective, antioxidant, anti-cancer, and anti-inflammatory activities. In this study, the in vitro hepatoprotective effect of lotus seedpod extract (LSE) and its main component epigallocatechin (EGC) was examined. Firstly, oleic acid (OA), an unsaturated fatty acid, was used to induce the phenotype of NAFLD in human hepatocytes, HepG2 cells. LSE dose-dependently improved the OA-induced viability loss of HepG2 cells. Non-cytotoxic concentrations of LSE or EGC abolished intracellular lipid accumulation and oxidative stress in the OA-treated cells. In addition, LSE and EGC showed a minor effect on autophagy, and potential in reducing OA-induced occurrence of apoptosis confirmed by morphological and biochemical features, including an increase in the formation of apoptotic bodies, the exposure of phosphatidylserine, and activation of caspases. Molecular data showed the anti-apoptotic effect of LSE might be mediated via downregulation of the mitochondrial pathway. Our data imply that EGC-enriched LSE potentially could be developed as an anti-NAFLD agent.

Physiopathologie des stéatoses hépatiques métaboliques

Non-Alcoholic Fatty Liver Disease (NAFLD) is a complex chronic disease resulting from an interaction between genetic and environmental factors. The phenotype and pathophysiology of NAFLD is heterogeneous. NAFLD is a continuum of histological lesions of the liver from steatosis, Non-Alcoholic SteatoHepatitis (NASH), NASH with fibrosis, cirrhosis to hepatocellular carcinoma. The pathophysiology encompasses a dysfunction in fatty tissue (sub-cutaneous and visceral) associated with insulin-resistance and metabolic inflammation. NAFLD is a "multi-systemic" disease. Reciprocal and aggravating interactions exist between NAFLD, cardiovascular anomalies and diabetes. The understanding of the mechanisms responsible for NAFLD allows the identification of potential novel therapeutic targets.

Sodium-glucose cotransporter 2 inhibition does not reduce hepatic steatosis in overweight, insulin-resistant patients without type 2 diabetes.

Background and AimNon‐alcoholic fatty liver disease (NAFLD) is rapidly becoming the leading indication for liver transplant and is associated with increased cardiovascular and liver mortality, yet there are no licensed therapies. Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are widely used for their glucose‐lowering effects in patients with type 2 diabetes (T2D). Preclinical models have suggested a beneficial impact on NAFLD, but clinical data are limited, and there are currently no data on patients without T2D. We aimed to investigate the impact of SGLT2 inhibition on NAFLD in overweight, nondiabetic patients and establish the effect these agents may have on the processes that regulate hepatic steatosis in vivo.MethodsWe conducted an open‐label, experimental medicine pilot study on insulin‐resistant overweight/obese individuals (n = 10) using gold‐standard noninvasive assessments of NAFLD phenotype, including magnetic resonance spectroscopy, two‐step hyperinsulinemic euglycemic clamps, and stable isotope tracers to assess lipid and glucose metabolism. Investigations were performed before and after a 12‐week treatment with the SGLT2 inhibitor, dapagliflozin.ResultsDespite a body weight reduction of 4.4 kg, hepatic steatosis was unchanged following treatment. Hepatic glucose production increased, and there was impairment of glucose disposal during the low‐dose insulin infusion. Although circulating, nonesterified, fatty acid levels did not change, the ability of insulin to suppress lipolysis was reduced.ConclusionsSGLT2 inhibition for 12 weeks does not improve hepatic steatosis in patients without T2D. Additional studies in patients with established T2D or impairments of fasting or postprandial glucose homeostasis are needed to determine whether SGLT2 inhibition represents a viable therapeutic strategy for NAFLD. (http://clinicaltrials.gov Number NCT02696941).

Inhibition of Mitochondrial Fatty Acid Oxidation Contributes to Development of Nonalcoholic Fatty Liver Disease Induced by Environmental Cadmium Exposure.

Cadmium (Cd) is one of the most prevalent toxic metal pollutants widely distributed in water and soil environments. Epidemiological studies have shown that exposure to Cd is implicated in the prevalence of nonalcoholic fatty liver disease (NAFLD) in middle-aged human population, but biological evidence is lacking and its toxicological mechanism remains unclear for the disease predisposition from environmental Cd exposure. In this study, we established a chronic Cd-exposure mouse model mimicking the liver Cd deposition in middle-aged human population to determine whether the environmental Cd exposure can induce NAFLD. Results showed that hepatic Cd burden at levels of 0.95 and 6.04 μg/g wet weight resulting from 20-week Cd exposure at different doses induced NAFLD and nonalcoholic steatohepatitis-like phenotypes in mice, respectively. The Cd exposure caused marked hepatic mitochondrial dysfunction and fatty acid oxidation deficiency, along with significant suppression of sirtuin 1 (SIRT1) signaling pathway in the liver. In vitro study confirmed that Cd evidently inhibited the mitochondrial fatty acid oxidation in hepatocytes and that SIRT1 signaling was potentially involved in the process. Our findings suggest that exposure to environmental Cd is a tangible risk factor for NAFLD, and the induced public health risks deserve greater attention.

Covering the Cover

Covering the Cover

Nicotinamide riboside exerts protective effect against aging-induced NAFLD-like hepatic dysfunction in mice.

Background & AimsAging is one of the risk factors of non-alcoholic fatty liver disease (NAFLD). Yet, the mechanism underlying the aging-associated NAFLD-like syndrome is not fully understood. Nicotinamide adenine dinucleotide (NAD), a ubiquitous coenzyme, has protective effects against aging. Here, we investigated the actions of NAD precursors nicotinamide riboside (NR) on the development of aging-induced NAFLD.MethodsNR supplemented food (2.5 g/kg food) was applied to aged mice for three months while normal chow to the other groups. Body weight, food intake, liver weight and fat pat mass were measured. The serum concentrations of lipid content, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and NAD were determined by biochemical assays. Pathological assessment and immunohistochemistry analysis of hepatic tissues were used to evaluate the effect of NR on NAFLD development and inflammatory infiltration.ResultsNR repletion significantly reduced fat pat mass in aged mice, while not altered the body weight, food intake, and liver weight. NR repletion significantly rescued the NAD reduction in aged mice. The total cholesterol and triglyceride levels could be lowered by NR repletion in aged mice. The AST level was also significantly reduced by NR repletion in aged group, while the ALT level lowered but without significance. Notably, moderate NAFLD phenotypes, including steatosis and hepatic fibrosis could be markedly corrected by NR repletion. In addition, Kupffer cells accumulated and inflammatory infiltration could also be remarkably reversed by NR repletion in aged mice.ConclusionAging was associated with NAFLD-like phenotypes in mice, which could be reversed by oral NR repletion. Therefore, oral NR uptake might be a promising strategy to halt the progression of NAFLD.

Combined Effects of Alcohol and Metabolic Disorders in Patients With Chronic Liver Disease

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the major causes for nonviral liver cirrhosis in the population. Whereas the typical NAFLD patient is one with abdominal obesity, metabolic syndrome (MetS), and no or minimal alcohol use, the patient with pure alcoholic liver cirrhosis has, according to cohort studies, typically consumed >5-10 daily alcohol drinks for several years.1 However, both alcohol use and components of the MetS are continuous variables and, as such, not dichotomic. Recent evidence suggests harmful synergistic effects of obesity, MetS, and alcohol intake for the risk of future liver disease.2 Consequently, given an increasing population prevalence of overweight and obese alcohol users, expectedly, there will be many patients that do not fit either the typical NAFLD or typical ALD phenotype, but share features of both disease entities. Current case-finding strategies focusing on either pure NAFLD or pure ALD3,4 may underestimate the true risk in individuals who will develop liver disease as the result of interaction between alcohol and metabolic disorders.1.

Non-invasive assessment of hepatic lipid subspecies matched with non-alcoholic fatty liver disease phenotype

Background and aimsNonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic fat accumulation. Increased hepatic saturated fats and decreased hepatic polyunsaturated fats may be particularly lipotoxic, contributing to metabolic dysfunction. We compared hepatic lipid subspecies in adults with and without NAFLD, and examined links with hallmark metabolic and clinical characteristics of NAFLD. Methods and resultsNineteen adults with NAFLD (total hepatic fat:18.8 ± 0.1%) were compared to sixteen adults without NAFLD (total hepatic fat: 2.1 ± 0.01%). 1H-MRS was used to assess hepatic lipid subspecies. Methyl, allylic, methylene, and diallylic proton peaks were measured. Saturation, unsaturation, and polyunsaturation indices were calculated. Whole-body phenotyping in a subset of participants included insulin sensitivity (40 mU/m2 hyperinsulinemic-euglycemic clamps), CT-measured abdominal adipose tissue depots, exercise capacity, and serum lipid profiles. Participants with NAFLD exhibited more saturated and less unsaturated hepatic fat, accompanied by increased insulin resistance, total and visceral adiposity, triglycerides, and reduced exercise capacity compared to controls (all P < 0.05). All proton lipid peaks were related to insulin resistance and hypertriglyceridemia (P < 0.05). ConclusionParticipants with NAFLD preferentially stored excess hepatic lipids as saturated fat, at the expense of unsaturated fat, compared to controls. This hepatic lipid profile was accompanied by an unhealthy metabolic phenotype.

Position statement on the diagnosis and management of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a major national and international health burden. It is one of the most common liver diseases worldwide and the most common cause of abnormal liver enzymes in many developed countries. Non-alcoholic fatty liver disease is also known as an important cause of cryptogenic cirrhosis and second leading cause for liver transplantation. It is commonly associated with metabolic syndrome. Non-alcoholic steatohepatitis (NASH) is the progressive phenotype of NAFLD. In spite of promising performance of non-invasive tools, liver biopsy remains the gold standard test for NASH diagnosis. Over decades, many drugs have been investigated in phase 2 and 3; however, no approved therapy to date. Despite the alarming global rates of NAFLD, there are no local community-based studies on the prevalence of NAFLD or local practice guidelines on its management; this expert review aims to fill this gap.