Review Articles Open access

From rare familial mutations to multifactorial disease: aldo-keto reductase 1C enzymes as a central biological pathway in lipedema

Authors

Published
20 April 2026
Section
Review Articles
DOI
10.4081/vl.2026.15495

Abstract

The discovery of pathogenic variants in AKR1C1 and AKR1C2 in ultra-rare familial lipedema highlights steroid hormone metabolism as a core mechanism affecting about 11% of women during reproductive age. Lipedema represents a complex disease shaped by the interplay between rare mutations, common regulatory variants, and environmental exposures. This review outlines how ultra-rare monogenic mutations can illuminate the genetic and environmental bases of multifactorial lipedema.

A systematic literature review (2000-2025) was performed using PubMed, Web of Science, and Google Scholar. Studies were identified with MeSH and keyword searches including lipedema, AKR1C1, AKR1C2, steroid metabolism, adipose tissue, obesogens, epigenetics, polycyclic aromatic hydrocarbons, endocrine disrupting chemicals, air pollution, and dietary hormones.

The AKR1C1 p.Leu213Gln loss-of-function variant decreases progesterone inactivation by ~50% due to catalytic domain destabilization, leading to local progesterone accumulation. AKR1C2 gain-of-function variants and overexpression, found in 24% of cases, enhance DHT inactivation, converting it to 3α-androstanediol and suppressing anti-adipogenic androgen signaling. Population screening revealed three AKR1C1 polymorphisms associated with increased lipedema risk. The AKR1C2 regulatory variant rs28571848 in a glucocorticoid receptor site elevates AKR1C2/AKR1C3 expression and trunk fat mass independently of BMI. Environmental agents such as polycyclic aromatic hydrocarbons activate AKR1C1 via Nrf2-ARE signaling (3-10-fold induction), while steroid hormones promote adipocyte differentiation.

Lipedema arises from an interaction between genetic susceptibility and environmental factors. Understanding the AKR1C pathway clarifies how genetic variants and obesogens disrupt steroid metabolism and induce epigenetic reprogramming, leading to clinical manifestations.

Keywords

References

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