A critical evaluation of the role of iron overload in fatty liver disease

Fernandez, Monique; Lokan, Julie; Leung, Christopher; Grigg, Andrew

doi:10.1111/jgh.15971

Cited by 19 publications

(13 citation statements)

References 47 publications

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“…--------------------------------------------------------------------------------------------------------------------- correlation between serum ferritin levels and HOMA-IR values in patients with NASH patients as well as those with CLD-C. Iron is likely to affect hepatic insulin sensitivity. It was thus hypothesized that the hepatic extraction and metabolism of insulin may be attenuated as the deposition of iron in the liver becomes more severe, leading to hyperinsulinemia in CLD-C and NASH (30,31). The present study revealed that serum Zn levels were inversely correlated with HOMA-IR values in patients with CLD-C (9).…”

Section: Discussionmentioning

confidence: 48%

Involvement of essential trace elements in the pathogenesis of hepatitis C virus‑related chronic liver disease and nonalcoholic steatohepatitis

Himoto,

Fujita,

Mimura

et al. 2023

Exp Ther Med

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Essential trace elements are involved in the pathogenesis of chronic liver disease (CLD), which causes hepatic inflammation, steatosis and fibrosis. The present study investigated the roles of essential trace elements in the pathogenesis of hepatitis C virus-related CLD (CLD-C) and nonalcoholic steatohepatitis (NASH), and compared the levels of these trace elements between the two groups. Serum zinc (Zn), selenium (Se), copper (Cu) and ferritin levels were measured in patients with CLD-C (n=66) and NASH (n=26). Subsequently, the correlations between the levels of these essential trace elements in patient sera and the biochemical or pathological parameters of patients with CLD-C and NASH were determined. The results demonstrated that the serum ferritin levels were significantly correlated with serum alanine aminotransferase levels in both the CLD-C and NASH groups. In both groups, the serum Zn and Se levels were significantly associated with serum albumin levels, and inversely associated with the stages of hepatic fibrosis. Furthermore, serum ferritin levels were positively associated, and serum Zn levels were inversely correlated with the grades of hepatic steatosis in patients with CLD-C, whereas serum Se levels were closely associated with the grades of hepatic steatosis only in patients with NASH. In both groups, serum ferritin levels were positively correlated, and serum Zn levels were inversely correlated with homeostasis model for the assessment of insulin resistance (HOMA-IR) values, and serum Se was negatively correlated with the HOMA-IR values in patients with CLD-C only. In conclusion, these results indicated that the involvement of essential trace elements in insulin resistance and hepatic steatosis may differ slightly between patients with CLD-C and those with NASH.

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Section: Discussionmentioning

confidence: 48%

Involvement of essential trace elements in the pathogenesis of hepatitis C virus‑related chronic liver disease and nonalcoholic steatohepatitis

Himoto,

Fujita,

Mimura

et al. 2023

Exp Ther Med

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“…This study notably utilized a much higher ferritin cut‐off (>750 ng/mL) and only included patients with positive liver iron staining (i.e., stage 2–3 MHF), suggestive of true hepatic iron overload, whereas our study had a lower ferritin cut‐off (primarily stage 1 MHF with less iron overload). Our findings apply to the more general MASLD population with mild hyperferritinaemia and may help explain the inconsistent effects of venesection in preventing disease progression in patients with MASLD and high ferritin levels 39 …”

Section: Discussionmentioning

confidence: 73%

Associations between metabolic hyperferritinaemia, fibrosis‐promoting alleles and clinical outcomes in steatotic liver disease

Suresh,

Li,

Miller

et al. 2023

Liver International

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Background & AimsFerritin has been investigated as a biomarker for liver fibrosis and iron in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). However, whether metabolic hyperferritinaemia predicts progression of liver disease remains unknown. In this study, we sought to understand associations between hyperferritinaemia and (1) adverse clinical outcomes and (2) common genetic variants related to iron metabolism and liver fibrosis.MethodsThis was a retrospective analysis of adults with MASLD seen at the University of Michigan Health System, where MASLD was defined by hepatic steatosis on imaging, biopsy or vibration‐controlled transient elastography, plus metabolic risk factors in the absence of chronic liver diseases other than hemochromatosis. The primary predictor was serum ferritin level, which was dichotomized based on a cut‐off of 300 or 450 mcg/L for women or men. Primary outcomes included (1) incident cirrhosis, liver‐related events, congestive heart failure (CHF), and mortality and (2) distribution of common genetic variants associated with hepatic fibrosis and hereditary hemochromatosis.ResultsOf 7333 patients with MASLD, 1468 (20%) had elevated ferritin. In multivariate analysis, ferritinaemia was associated with increased mortality (HR 1.68 [1.35–2.09], p < .001) and incident liver‐related events (HR 1.92 [1.11–3.32], p = .019). Furthermore, elevated ferritin was associated with carriage of cirrhosis‐promoting alleles including PNPLA3‐rs738409‐G allele (p = .0068) and TM6SF2‐rs58542926‐T allele (p = 0.0083) but not with common HFE mutations.ConclusionsIn MASLD patients, metabolic hyperferritinaemia was associated with increased mortality and higher incidence of liver‐related events, and cirrhosis‐promoting alleles but not with iron overload‐promoting HFE mutations.

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“…Recent studies have indicated that iron overload and associated oxidative stress are the primary causes of NAFLD [40][41][42]. However, the mechanisms underlying the regulation of ferroptosis in NAFLD and its correlation with fat accumulation are unclear.…”

Section: Discussionmentioning

confidence: 99%

FMO1 Promotes Nonalcoholic Fatty Liver Disease Progression by Regulating PPARα Activation and Inducing Ferroptosis

Zhang¹,

Shi²,

Li³

et al. 2023

Discovery Medicine

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Background: The function of flavin containing dimethylaniline monooxygenase 1 (FMO1), which is known to play a part in lipid metabolism, remains unclear in the development of nonalcoholic fatty liver disease (NAFLD). This research has the objective of examining the contributions of FMO1 in the progression of NAFLD and the associated mechanisms, particularly the peroxisome proliferator activated receptor alpha (PPARα) and ferroptosis pathways. Methods: An in vitro NAFLD model was established by treating L02 cells with free fatty acids (FFAs). The FMO1 and ferroptosis levels were examined in the cellular NAFLD model. FMO1 was knocked down using short-interfering RNA transfection. The effects of FMO1 knockdown on lipid accumulation, PPARα expression, and ferroptosis were examined in the cellular NAFLD model. Additionally, the effects of FMO1 and/or PPARα overexpression on lipid metabolism and ferroptosis were analyzed. Furthermore, L02 cells were pre-treated with GW7647 (PPARα agonist) or RSL3 (ferroptosis activator) and stimulated with FFAs. Results: The levels of FMO1 and ferroptosis were upregulated in the in vitro NAFLD model. FMO1 knockdown suppressed the FFA-induced accumulation of lipids in hepatocytes, downregulation of PPARα expression, and upregulation of ferroptosis. In contrast, FMO1 overexpression dysregulated lipid metabolism and downregulated PPARα levels. Meanwhile, PPARα overexpression mitigated the FMO1 overexpression-induced upregulation of ferroptosis and lipid accumulation. Treatment with RSL3 suppressed the effects of PPARα overexpression on lipid accumulation and FMO1 expression. Conclusions: FMO1 upregulates ferroptosis by suppressing PPARα in NAFLD, which leads to the dysregulation of lipid metabolism.

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A critical evaluation of the role of iron overload in fatty liver disease

Cited by 19 publications

References 47 publications

Involvement of essential trace elements in the pathogenesis of hepatitis C virus‑related chronic liver disease and nonalcoholic steatohepatitis

Involvement of essential trace elements in the pathogenesis of hepatitis C virus‑related chronic liver disease and nonalcoholic steatohepatitis

Associations between metabolic hyperferritinaemia, fibrosis‐promoting alleles and clinical outcomes in steatotic liver disease

FMO1 Promotes Nonalcoholic Fatty Liver Disease Progression by Regulating PPARα Activation and Inducing Ferroptosis

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