Redistribution of lamina-associated domains reshapes binding of pioneer factor FOXA2 in development of nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in type 2 diabetes mellitus and the elderly, impacting 40% of individuals over 70. Regulation of heterochromatin at the nuclear lamina has been associated with aging and age-dependent metabolic changes. We previously showed that changes at the lamina in aged hepatocytes and laminopathy models lead to redistribution of lamina-associated domains (LADs), opening of repressed chromatin, and up-regulation of genes regulating lipid synthesis and storage, culminating in fatty liver. Here, we test the hypothesis that change in the expression of lamina-associated proteins and nuclear shape leads to redistribution of LADs, followed by altered binding of pioneer factor FOXA2 and by up-regulation of lipid synthesis and storage, culminating in steatosis in younger NAFLD patients (aged 21–51). Changes in nuclear morphology alter LAD partitioning and reduced lamin B1 signal correlate with increased FOXA2 binding before severe steatosis in young mice placed on a western diet. Nuclear shape is also changed in younger NAFLD patients. LADs are redistrubted and lamin B1 signal decreases similarly in mild and severe steatosis. In contrast, FOXA2 binding is similar in normal and NAFLD patients with moderate steatosis and is repositioned only in NAFLD patients with more severe lipid accumulation. Hence, changes at the nuclear lamina reshape FOXA2 binding with progression of the disease. Our results suggest a role for nuclear lamina in etiology of NAFLD, irrespective of aging, with potential for improved stratification of patients and novel treatments aimed at restoring nuclear lamina function.

Interleukin-1ß Attenuates Expression of Augmenter of Liver Regeneration (ALR) by Regulating HNF4α Independent of c-Jun

“…Therefore, ALR plays an important role in NASH/fibrosis development, but the mechanism regulating ALR expression under these conditions is less clear. We and others found reduced expression of FOXA2 (HNF3ß), a transcription factor that positively regulates the expression of ALR [29], in the hepatic tissues of NASH patients [21,53]. In addition, here we present evidence that ALR is negatively regulated by IL-1ß, a cytokine that is known to be activated by inflammasomes, as well as oxidative stress, and is involved in the pathogenesis of NASH [8].…”

“…IL-6 was shown to enhance ALR expression by increasing the binding of FOXA2 to the ALR promoter [29]. On the other hand, FOXA2 expression and activity are low in NASH [21,53] and, therefore, high IL-6 levels might be without consequences. Additionally, TNFα was demonstrated to increase the release of ALR in an in vitro model [59] and therefore might contribute to low cellular levels in NASH and cholestasis.…”

Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: Primary and secondary gene responses with links to disease progression

“…S2B). Nuclei of TCPOBOP-exposed hepatocytes retained their characteristic round shape; they did not display the hepatocyte nuclear membrane deformation reported for a dietary model of mouse MASLD and in hepatocytes from MASLD patients, which was proposed to contribute to the activation of repressed genomic regions containing lipogenic genes in steatotic liver disease [55].…”

Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

“…Higher expression of LMNA causes activation of inflammatory NF-κB signaling, which leads to upregulation of adipokines such as TNF-α, IL6, IL10, and CCL2, resulting in insulin resistance to target cells. 238,239 In addition, insulin-dependent modulation of the interaction of FOXA2 with the lamina-associated domain (LAD) 240 and the interaction of CAV2 with LMNA 241 regulate the formation of the balance of nuclear laminaattached euchromatins and heterochromatins. The latter event is prompted by epigenetic modifications (demethylation of H3K9 and acetylation of histones) to activate transcription of gene sets that adjust insulin response in βsecretory cells and adipocytes.…”