Sexual Dimorphisms in Nonalcoholic Fatty Liver Disease

Musto, Jessica; Spengler, Erin; German, Margarita N.

doi:10.1007/s11901-021-00568-8

Cited by 3 publications

(4 citation statements)

References 94 publications

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Section: Discussionsupporting

confidence: 90%

“…In our sample, women had on average lower values of hepatic fat, less steatosis and less iron overload, which is in line with current knowledge about sex disparities in NAFLD prevalence. 7 However, we found stronger correlations of glucose markers with iron and fat content for women. Although NAFLD prevalence is lower in women, women are at a higher risk of progression to more severe disease states and advanced fibrosis, 26 which might be due to the loss of oestrogen and its anti-fibrotic effect during menopause.…”

Section: Discussionmentioning

confidence: 51%

“…5 Diabetes has also been identified as a risk factor of progression to liver cirrhosis and carcinoma. 6 However, although NAFLD development and progression are known to differ according to biological sex, 7 sex-specific impacts of diabetes on hepatic fat accumulation have not been comprehensively studied. Moreover, since glucose metabolism is dynamic, the development of glycaemia over time might also affect hepatic fat content.…”

Section: Backg Rou N Dmentioning

confidence: 99%

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Trajectories of glycaemic traits exhibit sex‐specific associations with hepatic iron and fat content: Results from the KORA‐MRI study

Niedermayer

Krüchten

et al. 2023

Liver International

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BackgroundNon‐alcoholic fatty liver disease (NAFLD) represents a major disease burden in the population. While the bidirectional association between NAFLD and diabetes is established, little is known about the association of hepatic iron content and glycaemia. Moreover, analyses of sex‐specific effects and of dynamic changes in glycaemia are scarce.MethodsWe investigated 7‐year sex‐specific trajectories of glycaemia and related traits (HbA1c, fasting glucose, fasting insulin, HOMA‐IR, 2‐h glucose and cross‐sectional 2‐h insulin) in a sample from a population‐based cohort (N = 365; 41.1% female). Hepatic iron and fat content were assessed by 3T‐Magnetic Resonance Imaging (MRI). Two‐step multi‐level models adjusted for glucose‐lowering medication and confounders were applied.ResultsIn women and men, markers of glucose metabolism correlated with hepatic iron and fat content. Deterioration of glycaemia was associated with increased hepatic iron content in men (normoglycaemia to prediabetes: beta = 2.21 s−1, 95% CI [0.47, 3.95]). Additionally, deterioration of glycaemia (e.g. prediabetes to diabetes: 1.27 log(%), [0.84, 1.70]) and trajectories of glucose, insulin and HOMA‐IR were significantly associated with hepatic fat content in men. Similarly, deterioration of glycaemia as well as trajectories of glucose, insulin and HOMA‐IR was significantly associated with increased hepatic fat content in women (e.g. trajectory of fasting insulin: 0.63 log(%), [0.36, 0.90]).ConclusionsUnfavourable 7‐year trajectories of markers of glucose metabolism are associated with increased hepatic fat content, particularly in women, whereas the association with hepatic iron content was less clear. Monitoring changes of glycaemia in the sub‐diabetic range might enable early identification of hepatic iron overload and steatosis.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 51%

Section: Backg Rou N Dmentioning

confidence: 99%

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Trajectories of glycaemic traits exhibit sex‐specific associations with hepatic iron and fat content: Results from the KORA‐MRI study

Niedermayer

Krüchten

et al. 2023

Liver International

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“…Males have a higher prevalence and severity of NAFLD as compared to females [ 42 ], and in females, increased androgen levels are associated with an elevated risk of NAFLD development and progression [ 30 , 43 ]. In animal models, females exposed to increased levels of androgens in utero develop NAFLD in adult life, indicating that androgens might be potential drivers of NAFLD development [ 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Hepatic Mitochondrial Dysfunction and Risk of Liver Disease in an Ovine Model of “PCOS Males”

et al. 2022

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First-degree male relatives of polycystic ovary syndrome (PCOS) sufferers can develop metabolic abnormalities evidenced by elevated circulating cholesterol and triglycerides, suggestive of a male PCOS equivalent. Similarly, male sheep overexposed to excess androgens in fetal life develop dyslipidaemia in adolescence. Dyslipidaemia, altered lipid metabolism, and dysfunctional hepatic mitochondria are associated with the development of non-alcoholic liver disease (NAFLD). We therefore dissected hepatic mitochondrial function and lipid metabolism in adolescent prenatally androgenized (PA) males from an ovine model of PCOS. Testosterone was directly administered to male ovine fetuses to create prenatal androgenic overexposure. Liver RNA sequencing and proteomics occurred at 6 months of age. Hepatic lipids, glycogen, ATP, reactive oxygen species (ROS), DNA damage, and collagen were assessed. Adolescent PA males had an increased accumulation of hepatic cholesterol and glycogen, together with perturbed glucose and fatty acid metabolism, mitochondrial dysfunction, with altered mitochondrial transport, decreased oxidative phosphorylation and ATP synthesis, and impaired mitophagy. Mitochondrial dysfunction in PA males was associated with increased hepatic ROS level and signs of early liver fibrosis, with clinical relevance to NAFLD progression. We conclude that excess in utero androgen exposure in male fetuses leads to a PCOS-like metabolic phenotype with dysregulated mitochondrial function and likely lifelong health sequelae.

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Childhood maltreatment and risk of metabolic dysfunction-associated steatotic liver disease – Evidence of sex-specific associations in the general population

Siewert-Markus,

Ittermann,

Klinger-König

et al. 2024

Journal of Psychosomatic Research

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Sexual Dimorphisms in Nonalcoholic Fatty Liver Disease

Cited by 3 publications

References 94 publications

Trajectories of glycaemic traits exhibit sex‐specific associations with hepatic iron and fat content: Results from the KORA‐MRI study

Trajectories of glycaemic traits exhibit sex‐specific associations with hepatic iron and fat content: Results from the KORA‐MRI study

Hepatic Mitochondrial Dysfunction and Risk of Liver Disease in an Ovine Model of “PCOS Males”

Childhood maltreatment and risk of metabolic dysfunction-associated steatotic liver disease – Evidence of sex-specific associations in the general population

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