Adipocyte retinoic acid receptor α prevents obesity and steatohepatitis by regulating energy expenditure and lipogenesis.

OBJECTIVE: The adipose tissue-liver axis is a major regulator of the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Retinoic acid signaling plays an important role in development and metabolism. However, little is known about the role of adipose retinoic acid signaling in the development of obesity-associated NAFLD. In this work, the aim was to investigate whether and how retinoic acid receptor alpha (RARα) regulated the development of obesity and NAFLD. METHODS: RARα expression in adipose tissue of db/db or ob/ob mice was determined. Rarαfl/fl mice and adipocyte-specific Rarα-/- (RarαAdi-/- ) mice were fed a chow diet for 1 year or high-fat diet (HFD) for 20 weeks. Primary adipocytes and primary hepatocytes were co-cultured. Metabolic regulation and inflammatory response were characterized. RESULTS: RARα expression was reduced in adipose tissue of db/db or ob/ob mice. RarαAdi-/- mice had increased obesity and steatohepatitis (NASH) when fed a chow diet or HFD. Loss of adipocyte RARα induced lipogenesis and inflammation in adipose tissue and the liver and reduced thermogenesis. In the co-culture studies, loss of RARα in adipocytes induced inflammatory and lipogenic programs in hepatocytes. CONCLUSIONS: The data demonstrate that RARα in adipocytes prevents obesity and NASH via inhibiting lipogenesis and inflammation and inducing energy expenditure.

Ferulic Acid Prevents Nonalcoholic Fatty Liver Disease by Promoting Fatty Acid Oxidation and Energy Expenditure in C57BL/6 Mice Fed a High-Fat Diet.

There is a consensus that ferulic acid (FA), the most prominent phenolic acid in whole grains, displays a protective effect in non-alcoholic fatty liver disease (NAFLD), though its underlying mechanism not fully elucidated. This study aimed to investigate the protective effect of FA on high-fat diet (HFD)-induced NAFLD in mice and its potential mechanism. C57BL/6 mice were divided into the control diet (CON) group, the HFD group, and the treatment (HFD+FA) group, fed with an HFD and FA (100 mg/kg/day) by oral gavage for 12 weeks. Hematoxylin and eosin (H&E) staining and Oil Red O staining were used to evaluate liver tissue pathological changes and lipid accumulation respectively. It was demonstrated that FA supplementation prevented HFD-induced NAFLD, which was evidenced by the decreased accumulation of lipid and hepatic steatosis in the HFD+FA group. Specifically, FA supplementation decreased hepatic triacylglycerol (TG) content by 33.5% (p < 0.01). Metabolic cage studies reveal that FA-treated mice have elevated energy expenditure by 11.5% during dark phases. Mechanistically, FA treatment increases the expression of rate-limiting enzymes of fatty acid oxidation and ketone body biosynthesis CPT1A, ACOX1 and HMGCS2, which are the peroxisome proliferator-activated receptors α (PPARα) targets in liver. In conclusion, FA could effectively prevent HFD-induced NAFLD possibly by activating PPARα to increase energy expenditure and decrease the accumulation of triacylglycerol in the liver.

A sustainable development goal framework to guide multisectoral action on NAFLD through a societal approach.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition that requires a comprehensive and coordinated response across sectors and disciplines. AIMS: In the absence of a multisectoral framework to tackle this condition, we developed one using the sustainable development goals (SDGs) as the basis for converging thinking about the design and delivery of public health responses. METHODS: A multidisciplinary group identified the SDG targets and indicators for inclusion in the new framework through a two-stage process. Firstly, a core team of three researchers independently reviewed the 169 targets and 231 indicators of the SDGs to select a shortlist. Over two Delphi rounds, a multidisciplinary group of 12 experts selected which of the shortlisted targets and indicators to include. Respondents also provided written feedback on their selection. Targets and indicators with 75% or greater agreement were included in the final framework. RESULTS: The final framework comprises 16 targets-representing 9% of all targets and 62% (16/26) of the shortlisted targets-and seven indicators, accounting for 50% (7/14) of the shortlisted indicators and 3% of all indicators. The selected targets and indicators cover a broad range of factors, from health, food and nutrition to education, the economy, and the built environment. CONCLUSIONS: Addressing the challenge of NAFLD will require a re-envisioning of the liver health landscape, with greater focus on joined-up systems thinking and action. This new framework can help guide this process, including by outlining the stakeholders with whom the liver health community needs to engage.

Hepatic de novo lipogenesis is suppressed and fat oxidation is increased by omega-3 fatty acids at the expense of glucose metabolism.

OBJECTIVE: Increased hepatic de novo lipogenesis (DNL) is suggested to be an underlying cause in the development of nonalcoholic fatty liver disease and/or insulin resistance. It is suggested that omega-3 fatty acids (FA) lower hepatic DNL. We investigated the effects of omega-3 FA supplementation on hepatic DNL and FA oxidation using a combination of human in vivo and in vitro studies. RESEARCH DESIGN AND METHODS: Thirty-eight healthy men were randomized to take either an omega-3 supplement (4 g/day eicosapentaenoic acid (EPA)+docosahexaenoic acid (DHA) as ethyl esters) or placebo (4 g/day olive oil) and fasting measurements were made at baseline and 8 weeks. The metabolic effects of omega-3 FAs on intrahepatocellular triacylglycerol (IHTAG) content, hepatic DNL and FA oxidation were investigated using metabolic substrates labeled with stable-isotope tracers. In vitro studies, using a human liver cell-line was undertaken to gain insight into the intrahepatocellular effects of omega-3 FAs. RESULTS: Fasting plasma TAG concentrations significantly decreased in the omega-3 group and remained unchanged in the placebo group. Eight weeks of omega-3 supplementation significantly decreased IHTAG, fasting and postprandial hepatic DNL while significantly increasing dietary FA oxidation and fasting and postprandial plasma glucose concentrations. In vitro studies supported the in vivo findings of omega-3 FAs (EPA+DHA) decreasing intracellular TAG through a shift in cellular metabolism away from FA esterification toward oxidation. CONCLUSIONS: Omega-3 supplementation had a potent effect on decreasing hepatic DNL and increasing FA oxidation and plasma glucose concentrations. Attenuation of hepatic DNL may be considered advantageous; however, consideration is required as to what the potential excess of nonlipid substrates (eg, glucose) will have on intrahepatic and extrahepatic metabolic pathways. TRIAL REGISTRATION NUMBER: NCT01936779.

A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and has become an important field of biomedical inquiry. We aimed to determine whether European countries have mounted an adequate public health response to NAFLD and non-alcoholic steatohepatitis (NASH). METHODS: In 2018 and 2019, NAFLD experts in 29 European countries completed an English-language survey on policies, guidelines, awareness, monitoring, diagnosis and clinical assessment in their country. The data were compiled, quality checked against existing official documents and reported descriptively. RESULTS: None of the 29 participating countries had written strategies or action plans for NAFLD. Two countries (7%) had mentions of NAFLD or NASH in related existing strategies (obesity and alcohol). Ten (34%) reported having national clinical guidelines specifically addressing NAFLD and, upon diagnosis, all included recommendations for the assessment of diabetes and liver cirrhosis. Eleven countries (38%) recommended screening for NAFLD in all patients with either diabetes, obesity and/or metabolic syndrome. Five countries (17%) had referral algorithms for follow-up and specialist referral in primary care, and 7 (24%) reported structured lifestyle programmes aimed at NAFLD. Seven (24%) had funded awareness campaigns that specifically included prevention of liver disease. Four countries (14%) reported having civil society groups which address NAFLD and 3 countries (10%) had national registries that include NAFLD. CONCLUSIONS: We found that a comprehensive public health response to NAFLD is lacking in the surveyed European countries. This includes policy in the form of a strategy, clinical guidelines, awareness campaigns, civil society involvement, and health systems organisation, including registries. LAY SUMMARY: We conducted a survey on non-alcoholic fatty liver disease with experts in European countries, coupled with data extracted from official documents on policies, clinical guidelines, awareness, and monitoring. We found a general lack of national policies, awareness campaigns and civil society involvement, and few epidemiological registries.

Dietary Patterns and Components in Nonalcoholic Fatty Liver Disease (NAFLD): What Key Messages Can Health Care Providers Offer?

Nonalcoholic fatty liver disease (NAFLD) is a rising epidemic worldwide and will be the leading cause of cirrhosis, hepatocellular carcinoma, and liver transplant within the next decade. NAFLD is considered as the hepatic manifestation of metabolic syndrome. Behaviors, such as a sedentary lifestyle and consuming a Western diet, have led to substantial challenges in managing NAFLD patients. With no curative pharmaceutical therapies, lifestyle modifications, including dietary changes and exercise, that ultimately lead to weight loss remain the only effective therapy for NAFLD. Multiple diets, including low-carbohydrate, low-fat, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean (MD) diets, have been evaluated. NAFLD patients have shown better outcomes with a modified diet, such as the MD diet, where patients are encouraged to increase the consumption of fruits and vegetables, whole grains, and olive oil. It is increasingly clear that a personalized approach to managing NAFLD patients, based on their preferences and needs, should be implemented. In our review, we cover NAFLD management, with a specific focus on dietary patterns and their components. We emphasize the successful approaches highlighted in recent studies to provide recommendations that health care providers could apply in managing their NAFLD patients.

Alcoholic and non-alcoholic steatohepatitis: global perspective and emerging science.

Alcohol and high-fat diet are two major risk factors responsible for metabolic diseases, which are manifested as steatohepatitis and liver cancer in the liver, and chronic pancreatitis and pancreatic adenocarcinoma (PDAC) in the pancreas. These metabolic diseases are becoming increasingly prevalent around the globe, and more importantly, their two major etiologies commonly coexist to precipitate the disease processes. To highlight the importance of these metabolic diseases, Japanese Society of Gastroenterology (JSGE) and National Institute on Alcoholism and Alcohol Abuse of National Institute of Health cosponsored the JSGE's 7th International Forum jointly held with the 12th International Symposium on ALPD and Cirrhosis. Toward the main theme of "Frontiers in ASH, NASH, NBNC-HCC and PDAC", this platform showcased presentations by 12 invited international and Japanese speakers on brain-gut-liver interactions, emerging mechanisms of ASH and NASH, metabolic reprogramming, and new therapeutic targets for cirrhosis, HCC, and PDAC. This editorial discusses the most recent data on global statistics on how alcohol and obesity impact health and longevity as a prelude to a brief summary of the symposium presentations and discussions, primarily focusing on the first two session themes.

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.

NAFLD is one of the most important causes of liver disease worldwide and will probably emerge as the leading cause of end-stage liver disease in the coming decades, with the disease affecting both adults and children. The epidemiology and demographic characteristics of NAFLD vary worldwide, usually parallel to the prevalence of obesity, but a substantial proportion of patients are lean. The large number of patients with NAFLD with potential for progressive liver disease creates challenges for screening, as the diagnosis of NASH necessitates invasive liver biopsy. Furthermore, individuals with NAFLD have a high frequency of metabolic comorbidities and could place a growing strain on health-care systems from their need for management. While awaiting the development effective therapies, this disease warrants the attention of primary care physicians, specialists and health policy makers.

Health and economic benefits of reducing sugar intake in the USA, including effects via non-alcoholic fatty liver disease: a microsimulation model.

OBJECTIVES: Excessive consumption of added sugars in the human diet has been associated with obesity, type 2 diabetes (T2D), coronary heart disease (CHD) and other elements of the metabolic syndrome. Recent studies have shown that non-alcoholic fatty liver disease (NAFLD) is a critical pathway to metabolic syndrome. This model assesses the health and economic benefits of interventions aimed at reducing intake of added sugars. METHODS: Using data from US National Health Surveys and current literature, we simulated an open cohort, for the period 2015-2035. We constructed a microsimulation model with Markov chains for NAFLD (including steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC)), body mass index, T2D and CHD. We assessed reductions in population disease prevalence, disease-attributable disability-adjusted life years (DALYs) and costs, with interventions that reduce added sugars consumption by either 20% or 50%. FINDINGS: The model estimated that a 20% reduction in added sugars intake will reduce prevalence of hepatic steatosis, NASH, cirrhosis, HCC, obesity, T2D and CHD. Incidence of T2D and CHD would be expected to decrease by 19.9 (95% CI 12.8 to 27.0) and 9.4 (95% CI 3.1 to 15.8) cases per 100 000 people after 20 years, respectively. A 20% reduction in consumption is also projected to annually avert 0.767 million (M) DALYs (95% CI 0.757M to 0.777M) and a total of US$10.3 billion (B) (95% CI 10.2B to 10.4B) in discounted direct medical costs by 2035. These effects increased proportionally when added sugars intake were reduced by 50%. CONCLUSIONS: The decrease in incidence and prevalence of disease is similar to results in other models, but averted costs and DALYs were higher, mainly due to inclusion of NAFLD and CHD. The model suggests that efforts to reduce consumption of added sugars may result in significant public health and economic benefits.

Health Benefits of Long-Term Weight-Loss Maintenance.

Obesity is a chronic and complex medical condition associated with a large number of complications affecting most organs and systems through multiple pathways. Strategies for weight management include behavioral, pharmacological, and surgical interventions, all of which can result in a reduction in obesity-related comorbidities and improvements in quality of life. However, subsequent weight regain often reduces the durability of these improvements. The objective of this article is to review evidence supporting the long-term effects of intentional weight loss on morbidity, mortality, quality of life, and health-care cost. Overall, considerable evidence suggests that intentional weight loss is associated with clinically relevant benefits for the majority of obesity-related comorbidities. However, the degree of weight loss that must be achieved and sustained to reap these benefits varies widely between comorbidities.

The imperative to prevent diabetes complications: a broadening spectrum and an increasing burden despite improved outcomes.

Diabetes mellitus and its complications are common; the complications are, of themselves, a major reason to manage diabetes. Recent data from Australia and similar developed health care systems overseas indicate that morbidity and mortality outcomes relating to diabetes complications are improving. However, these benefits are offset by increasing numbers of people diagnosed with diabetes, resulting in an increased disease burden with significant health care implications. Thus the imperative to prevent diabetes and diabetes complications has never been greater. Furthermore, the recognised spectrum of diabetes complications is broadening, especially complications relating to lipid levels, insulin resistance and the metabolic syndrome. Clinicians now need to be aware of both traditional complications (eg, nephropathy and cardiovascular disease) and non-traditional complications (eg, polycystic ovary syndrome, non-alcoholic fatty liver disease, some cancers and eating disorders). Complications outcomes could be further improved by decreasing the evidence-treatment gap - for example, by increasing personalisation of care in managing diabetes complications.