Hypopharyngeal Squamous Cell Carcinoma in Sisters with LMNA Associated Familial Partial Lipodystrophy: A Case Report and Review of the Literature

Youssef, Stephanie J.; Macielak, Robert J.; Schimmenti, Lisa A.; Chatzopoulos, Kyriakos; Price, Daniel L.

doi:10.1177/0003489420933645

Cited by 3 publications

(2 citation statements)

References 11 publications

(27 reference statements)

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“…However, the relationship between lipid metabolism and LMNA regulation remains unknown. A case report noted that two biological sisters with LMNA-mutant FPLD developed hypopharyngeal squamous cell carcinoma [24].…”

Section: Introductionmentioning

confidence: 99%

Abnormal in LMNA Triggers a Shift in Intracellular Metabolic Homeostasis Via AMPK Activation

Zhao¹,

Yang²,

Cheng³

et al. 2022

Preprint

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Laminopathies are a spectrum of diseases caused by LMNA mutations. In familial partial lipodystrophy of Dunnigan (FPLD), LMNA plays role in the differentiation and development of adipocytes and lipid metabolism. Changes in LMNA predict not only the differentiation of adipose-derived mesenchymal stem cells (AD-MSCs) but also the transformation of cancer cells. Hence, our in-depth study aimed to identify the molecular connection between disordered lipid metabolism and hepatic carcinogenesis. We first discovered significant positive correlations between pLMNA and two key rate-limiting enzymes in de novo fatty acid synthesis, acetyl-CoA-carboxylase 1 (ACC1) and fatty acid synthase (FASN), in the liver tissue but not in adipose tissue of obese model rats. Moreover, LMNA knockdown (KD) in rat AD-MSCs prevented the differentiation and maturation of adipocytes. To clarify the mechanistic relationship with lipogenesis, gain- and loss-of-function experiments in which functional changes and the related molecular pathways were investigated in a normal hepatocyte line (7701 cells). Adenosine 5'-monophosphate activated protein kinase α (AMPKα) was found to be activated by abnormalities in the LMNA structure under conditions of LMNA deletion, farnesyltransferase inhibitor (FTI) treatment and LMNA mutations associated with clinical FPLD pathogenic phenotype. Active AMPKα could directly phosphorylate ACC1 and thus inhibit lipid synthesis but induced glycolysis in both HCC cells and normal cells. The HCC cells could not survive with LMNA knockout (KO) or even KD. Lonafarnib (an FTI) combined with low-glucose conditions significantly decreased the proliferation of HepG2 and MHCC cells by inhibiting glycolysis and the maturation of prelamin A.

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Section: Introductionmentioning

confidence: 99%

Abnormal in LMNA Triggers a Shift in Intracellular Metabolic Homeostasis Via AMPK Activation

Zhao¹,

Yang²,

Cheng³

et al. 2022

Preprint

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“…However, the relationship between lipid metabolism and lamin A/C regulation remains unknown. A case report noted that two biological sisters with LMNA -mutant FPLD developed hypopharyngeal squamous cell carcinoma [ 26 ]. This study inspired us to focus on the role of lamin A/C in lipid metabolism associated with metabolic syndrome and HCC.…”

Section: Introductionmentioning

confidence: 99%

Loss of Mature Lamin A/C Triggers a Shift in Intracellular Metabolic Homeostasis via AMPKα Activation

Zhou

Yang

Cheng

et al. 2022

Cells

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The roles of lamin A/C in adipocyte differentiation and skeletal muscle lipid metabolism are associated with familial partial lipodystrophy of Dunnigan (FPLD). We confirmed that LMNA knockdown (KD) in mouse adipose-derived mesenchymal stem cells (AD-MSCs) prevented adipocyte maturation. Importantly, in in vitro experiments, we discovered a significant increase in phosphorylated lamin A/C levels at serine 22 or 392 sites (pLamin A/C-S22/392) accompanying increased lipid synthesis in a liver cell line (7701 cells) and two hepatocellular carcinoma (HCC) cell lines (HepG2 and MHCC97-H cells). Moreover, HCC cells did not survive after LMNA knockout (KO) or even KD. Evidently, the functions of lamin A/C differ between the liver and adipose tissue. To date, the mechanism of hepatocyte lipid metabolism mediated by nuclear lamin A/C remains unclear. Our in-depth study aimed to identify the molecular connection between lamin A/C and pLamin A/C, hepatic lipid metabolism and liver cancer. Gain- and loss-of-function experiments were performed to investigate functional changes and the related molecular pathways in 7701 cells. Adenosine 5’ monophosphate-activated protein kinase α (AMPKα) was activated when abnormalities in functional lamin A/C were observed following lamin A/C depletion or farnesyltransferase inhibitor (FTI) treatment. Active AMPKα directly phosphorylated acetyl-CoA-carboxylase 1 (ACC1) and subsequently inhibited lipid synthesis but induced glycolysis in both HCC cells and normal cells. According to the mass spectrometry analysis, lamin A/C potentially regulated AMPKα activation through its chaperone proteins, ATPase or ADP/ATP transporter 2. Lonafarnib (an FTI) combined with low-glucose conditions significantly decreased the proliferation of the two HCC cell lines more efficiently than lonafarnib alone by inhibiting glycolysis or the maturation of prelamin A.

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Clinical Spectrum of LMNA-Associated Type 2 Familial Partial Lipodystrophy: A Systematic Review

Fernández-Pombo

Díaz-López

Castro

et al. 2023

Cells

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Type 2 familial partial lipodystrophy (FPLD2) is a laminopathic lipodystrophy due to pathogenic variants in the LMNA gene. Its rarity implies that it is not well-known. The aim of this review was to explore the published data regarding the clinical characterisation of this syndrome in order to better describe FPLD2. For this purpose, a systematic review through a search on PubMed until December 2022 was conducted and the references of the retrieved articles were also screened. A total of 113 articles were included. FPLD2 is characterised by the loss of fat starting around puberty in women, affecting limbs and trunk, and its accumulation in the face, neck and abdominal viscera. This adipose tissue dysfunction conditions the development of metabolic complications associated with insulin resistance, such as diabetes, dyslipidaemia, fatty liver disease, cardiovascular disease, and reproductive disorders. However, a great degree of phenotypical variability has been described. Therapeutic approaches are directed towards the associated comorbidities, and recent treatment modalities have been explored. A comprehensive comparison between FPLD2 and other FPLD subtypes can also be found in the present review. This review aimed to contribute towards augmenting knowledge of the natural history of FPLD2 by bringing together the main clinical research in this field.

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Hypopharyngeal Squamous Cell Carcinoma in Sisters with LMNA Associated Familial Partial Lipodystrophy: A Case Report and Review of the Literature

Cited by 3 publications

References 11 publications

Abnormal in LMNA Triggers a Shift in Intracellular Metabolic Homeostasis Via AMPK Activation

Abnormal in LMNA Triggers a Shift in Intracellular Metabolic Homeostasis Via AMPK Activation

Loss of Mature Lamin A/C Triggers a Shift in Intracellular Metabolic Homeostasis via AMPKα Activation

Clinical Spectrum of LMNA-Associated Type 2 Familial Partial Lipodystrophy: A Systematic Review

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