Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps

Lonardo, Amedeo; Nascimbeni, Fabio; Ballestri, Stefano; Fairweather, De Lisa; Win, Sanda; Than, Tin Aung; Abdelmalek, Manal F.; Suzuki, Ayako

doi:10.1002/hep.30626

Cited by 653 publications

(644 citation statements)

References 94 publications

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“…Mice were fasted for 5 hours prior to intraperitoneal injection with insulin Humulin R (Eli Lilly, IN, USA) at 0.7 IU/kg body weight or 0.5 IU/kg body weight for males and females, respectively. Blood glucose levels were taken from tail vein using a Freestyle Lite glucometer (Abbott, IL, USA) at 0, 15,30,45,60,90 and 120 minutes post-injection.…”

Section: Nash Cohort Diets and Micementioning

confidence: 99%

Differences in metabolic and liver pathobiology induced by two dietary mouse models of nonalcoholic fatty liver disease

Zhang¹,

Léveillé²,

Courty³

et al. 2020

Preprint

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Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic associated with key aspects of metabolic disease such as obesity and diabetes. The first stage of NAFLD is characterized by lipid accumulation in hepatocytes, but this can further progress into non-alcoholic steatohepatitis (NASH), fibrosis or cirrhosis, and hepatocellular carcinoma (HCC). A western diet, high in fats, sugars and cholesterol is linked to NAFLD development. Murine models are often used to experimentally study NAFLD, as they can display similar histopathological features as humans;however, there remains debate on which diet-induced model most appropriately and consistently mimics both human disease progression and pathogenesis. In this study, we performed a side-byside comparison of two popular diet models of murine NAFLD/NASH and associated HCC: a high fat diet supplemented with 30% fructose water (HFHF) and a western diet high in cholesterol (WDHC), comparing them to a common grain-based chow diet (GBD). Mice on both experimental diets developed liver steatosis, while WDHC-fed mice had greater levels of hepatic inflammation and fibrosis than HFHF-fed mice. In contrast, HFHF-fed mice were more obese and developed more severe metabolic syndrome, with less pronounced liver disease. Despite these differences, WDHC-fed and HFHF-fed mice had similar tumour burdens in a model of diet-potentiated liver cancer. Response to diet and resulting phenotypes were generally similar between sexes, albeit delayed in females. Notably, although metabolic and liver disease phenotypes are often thought to progress in parallel, this study shows that modest differences in diet can significantly uncouple glucose homeostasis and liver damage. In conclusion, long-term feeding of either HFHF or WDHC are reliable methods to induce NASH and diet-potentiated liver cancer in mice of both sexes; however, the choice of diet involves a trade-off between severity of metabolic syndrome and liver damage. HCC Mouse CohortWild-type inbred C57BL/6N genetic background mice were housed in the same fashion as the NASH cohort mice described above. Mice were injected with 25 mg of diethylnitrosamine (DEN) per kg body mass at 2 weeks of age. Mice were fed ad libitum either the HFHF diet or the WDHC diet as described above. 14 males (n=6 on HFHF, n=8 on WDHC) and 14 females (n=7 on HFHF and n=7 on WDHC). Body mass was taken weekly, and mice were sacrificed after 24 weeks of feeding following a 3-hour fast. Samples were processed in a similar manner as the NASH cohort. Blood CollectionA minimum concentration of 3.2 µL per 600 µL blood of Aprotinin from bovine lung (Sigma, MA, USA) was added to all blood samples (except those taken during the glucose tolerance test) to prevent protein degradation. Blood collected during the oral glucose tolerance test (OGTT) was collected in Microvette Ò 100µL K3 EDTA (Sarstedt, Germany). Blood was incubated at 4°C for 90 minutes, followed by an 8-minute centrifugation at 4000 rpm at 4°C. The top layer of serum was collected and stored at -80°C unti...

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Section: Nash Cohort Diets and Micementioning

confidence: 99%

Differences in metabolic and liver pathobiology induced by two dietary mouse models of nonalcoholic fatty liver disease

Zhang¹,

Léveillé²,

Courty³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…These studies support the idea that healthy dietary patterns can be helpful for patients with metabolic risk factors. Recently published data have identified sex‐based influence on NAFLD and therefore, NAFLD is a sexually dimorphic disease . In addition, there may be a difference in diet quality between men and women, an epiphenomenon.…”

Section: Introductionmentioning

confidence: 99%

“…Recently published data have identified sex-based influence on NAFLD and therefore, NAFLD is a sexually dimorphic disease. 22,23 In addition, there may be a difference in diet quality between men and women, an epiphenomenon.…”

Section: Introductionmentioning

confidence: 99%

Diet quality and its association with nonalcoholic fatty liver disease and all‐cause and cause‐specific mortality

Yoo

Kim

Vazquez‐Montesino

et al. 2020

Liver International

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Background & Aims Healthy diet has been recommended for nonalcoholic fatty liver disease (NAFLD), although it is not clear whether improving diet quality can prevent mortality. We aim to assess the impact of quality of diet on NAFLD and mortality in subjects with and without NAFLD. Methods We performed cohort study using the Third National Health and Nutrition Examination Survey from 1988 to 1994 and linked mortality data through 2015. We used the Healthy Eating Index (HEI) scores to define diet quality, with higher HEI scores (Q4) indicating better adherence to dietary recommendations. NAFLD was defined as ultrasonographic hepatic steatosis. Results Multivariate analysis showed that subjects with higher diet quality were inversely associated with NAFLD in a dose‐dependent manner. During the median follow‐up of 23 years, having a higher diet quality was associated with reduction in risk of all‐cause mortality in the age, sex, Race/ethnicity‐adjusted hazard ratio (HR) (Q4, HR: 0.60, 95% CI: 0.52‐0.68) and the multivariate model (Q4, HR: 0.81, 95% CI: 0.71‐0.92). Higher diet quality was associated with a lower risk for all‐cause mortality in subjects without NAFLD; however, this protective association with diet quality was not noted in those with NAFLD. Furthermore, a high diet quality was associated with a lower risk for cancer‐related mortality in the total population and among those without NAFLD. This association was not noted in those with NAFLD. Conclusions High diet quality was inversely associated with NAFLD and was positively associated with a lower risk for cancer‐related and all‐cause mortality in those without NAFLD.

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“…However, muscle insulin sensitivity is not different between the sexes [106]. Future clinical trials should be designed to test drug efficacy and safety according to sex, age, reproductive stage (i.e., menopause), and synthetic hormone use [107]. We should be prepared to provide any sex-specific therapeutic approaches to NASH patients with T2D.…”

Section: Precision Medicine In the Treatment Strategy Of Nashmentioning

confidence: 99%

Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis

Sumida

Yoneda

Tokushige

et al. 2020

IJMS

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Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are Int.expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D.

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Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps

Cited by 653 publications

References 94 publications

Differences in metabolic and liver pathobiology induced by two dietary mouse models of nonalcoholic fatty liver disease

Differences in metabolic and liver pathobiology induced by two dietary mouse models of nonalcoholic fatty liver disease

Diet quality and its association with nonalcoholic fatty liver disease and all‐cause and cause‐specific mortality

Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis

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