ABSTRACT
Relationship between
hypoxia inducible factor-1 alpha (HIF-1α) levels and cellulite
Angela Fovina1*, Nelva Karmila Jusuf2, Imam Budi Putra2
Background: Cellulite is a topographic change of the skin surface, characterized by an appearance like orange peel, mattress or cottage cheese, especially on the buttocks and hamstrings. Cellulite is a process that starts from adipocyte hypertrophy and dermal vascular damage, especially loss of the capillary network. Loss of the capillary network will cause the dermis and subcutaneous tissue to retain fluid, inhibiting venous return and causing swelling, ischemia, and hypoxia in the subcutaneous tissue. When hypoxia occurs, cellular adaptive processes activate hypoxia-inducible factor (HIF). Hypoxia-inducible factor-1α will interact with enzymes and other transcription factors to maintain homeostasis by increasing vascularization and tissue growth in acute hypoxic conditions. However, in chronic hypoxic conditions, HIF-1α can cause detrimental effects such as excessive extracellular matrix development resulting in tissue fibrosis. This study aims to determine the relationship between HIF-1α levels and cellulite.
Methods: This observational research included 40 cellulite patients and 40 controls in a cross-sectional design. Each patient got a medical history check, a dermatological exam, and blood testing to determine their HIF-1 levels using an ELISA test. The Chi-square test was used to statistically analyze these statistics.
Results: The mean HIF-1α level in cellulite was 5.74±2.39 ng/ml. The highest age with cellulite was 26–33 years, consisting of 12 (30%) people. Most of them had a family history of cellulite from their mother, consisting of 15 (37.5%) people. Nineteen (47.5%) of them were obese. Most cellulite is located on the femoral and gluteus regions in 27 people (67.5%). The result of this study showed that there was a relationship between high HIF-1α levels causing a risk of 4.8 times for cellulite (p=0.002).
Conclusion: There is a relationship between HIF-1α levels and cellulite.
Keywords: cellulite, Hypoxia Inducible Factor-1 alpha, HIF-1α levels.
Cite This Article: Fovina, A., Jusuf, N.K., Putra, I.B. 2023. Relationship between hypoxia inducible factor-1 alpha (HIF-1α) levels and cellulite. Bali Medical Journal 12(2): 1724-1728. DOI: 10.15562/bmj.v12i2.4247
1Postgraduate Master of Clinical Medicine Department of Dermatology and Venereology, Faculty of Medicine, Universitas Sumatera Utara, Universitas Sumatera Utara Hospital, Medan, Indonesia;
2Department of Dermatology and Venereology, Faculty of Medicine, Universitas Sumatera Utara, Universitas Sumatera Utara Hospital, Medan, Indonesia.
*Corresponding author:
Angela Fovina;
Postgraduate Master of Clinical Medicine Department of Dermatology and Venereology, Faculty of Medicine, Universitas Sumatera Utara, Universitas Sumatera Utara Hospital, Medan, Indonesia;
[email protected] Received: 2023-03-11 Accepted: 2023-04-25 Published: 2023-05-29
INTRODUCTION
Specifically on the buttocks and hamstrings, cellulite is a topographic shift of the skin’s surface that has an orange peel, mattress, or cottage cheese appearance.1 Around 80–90% of postpubertal females of all races, particularly Caucasians, can have cellulite. The search for underlying causes of blood vessels and metabolic processes in the subcutaneous tissue linked to chronic ischemia has been sparked by recent research on the pathogenesis of cellulite.1,2 Cellulite is a process that starts from adipocyte hypertrophy and dermal vascular damage, especially loss of the capillary network. The dermis and subcutaneous tissue will hold fluid as a result of the capillary network being lost, which will prevent venous return and result in swelling, ischemia, and hypoxia
in the subcutaneous tissue.3,4
Hypoxia-inducible factor (HIF), a dimer consisting of 120 kDa oxygen- regulated -subunit and 91-94 kDa β-subunit, is activated by cellular adaptive processes when hypoxia happens. The HIF-β subunit is an unresponsive core protein on the tissue oxygenation level, whereas hypoxic conditions strongly induce HIF-1α.5
Hypoxia-inducible factor-1α will interact with enzymes and other transcription factors to maintain homeostasis by increasing vascularization and tissue growth in acute hypoxic conditions.6 However, in chronic hypoxic conditions, HIF-1α can cause detrimental effects such as excessive extracellular matrix development resulting in tissue fibrosis.7
HIF-1 expression in fat tissue contributes to the growth of local fibrosis and inflammation. One study found that women with this specific polymorphism did not acquire cellulite or did so to a very low degree. The T allele of the rs11549465 polymorphism to HIF1A reduced HIF1A activity in patients. This connection shows how cellulite and HIF-1 are related, and it also shows how reduced local microcirculation and cellulite development are related.2,3
Based on the explanation above, there is a hypothesis that HIF has a role in the pathophysiology of cellulite, but it is still limited, so research is needed to determine the relationship between HIF-1α levels and cellulite. Thus, this study aimed to determine the relationship between HIF- 1α levels and cellulite.
METHODS
Patient and study design
Forty cellulite patients and 40 controls, aged 18 to 50, participated in this analytic observational research with a cross- sectional design at the Dermatology and Venereology polyclinic at Universitas Sumatera Utara, Medan in 2022. This study used purposive sampling method and included every research subject who provided informed consent. Pregnant and nursing women, malignancy, hypertension, coronary heart disease, diabetes mellitus, psoriasis, and keloid- related conditions were excluded. After receiving approval from the Research Division of the Universitas Sumatera Utara Hospital and ethical clearance from the Universitas Sumatera Utara Research Ethics Commission, this research was carried out.
Data Collection
Researchers gathered the data at the Dermatology and Venereology polyclinic in Universitas Sumatera Utara, Medan, where patients visit. To evaluate serum HIF-1, researchers carefully review the patient’s medical history, conduct a clinical examination, and draw blood. Human HIF-1 Elisa Kit was used to detect serum HIF-1 levels.
Statistical analysis
The Chi-square test was used to analyze the data to determine the association between serum HIF-1 levels and cellulite, with a significance level of 0.05 being deemed significant.
RESULTS
This study divided the subjects into cellulite and control groups (with no cellulite). The characteristics of the subjects based on age are presented in Table 1. Most of the research subjects in the cellulite group were 26–33 years old (30%), while most of the control group were 18–25 years old (57.5%). According to family history, the majority of the cellulite group had a family history from their mother, 15 people (37.5%), and most of the control group had no family history, consisting of 28 people (70%) (Table 2).
Table 3 shows the characteristics of
Table 1. Distribution of research subjects by age
Age (years) Cellulite patients Control
n % n %
18–25 10 25 23 57.5
26–33 12 30 8 20
34–41 10 25 7 17.5
42–50 8 20 2 5
Total 40 100 40 100
Table 2. Distribution of research subjects by family history
Family History Cellulite patients Control
n % n %
Mother 15 37.5 6 15
Sibling 14 35 3 7.5
Mother and sibling 6 15 3 7.5
No family history 5 12.5 28 70
Total 40 100 40 100
Table 3. Distribution of research subjects by BMI
BMI Cellulite patients Control
n % n %
Normal 8 20 26 65
Overweight 13 32.5 10 25
Obesity 19 47.5 4 10
Total 40 100 40 100
Table 4. Distribution of research subjects by location of cellulite
Cellulite Locations Cellulite patients
n %
Femoralis 2 5
Femoralis and gluteus 27 67.5
Femoralis, gluteus, and abdominalis 11 27.5
Total 40 100
Table 5. Average HIF-1α levels in study subjects
Group HIF-1α levels
n Mean SD
Cellulite 40 5.74 2.39
Control 40 3.90 1.22
Table 6. Relationship between HIF-1α levels and cellulite
HIF-1α levels Group
Odd p-value
Cellulite Control
Low 12 (15%) 27 (33.8%) 4.8 0.002
High 28 (35%) 13 (16.2%)
Total 40 (50%) 40 (50%)
subjects based on BMI in this study. It was stated that the majority of obese in the cellulite group were 19 people (47.5%), followed by overweight 13 people (32.5%), and normal was 8 people (20%). Most of the control group had a normal BMI of 26 people (65%). We found that cellulite was present in 27 (67.5%) of the individuals on the femoral and gluteal areas, 11 (27.5%)
on the femoral, gluteal, and abdominal areas, and 2 (5%) on the femoral areas (Table 4).
Then, an ELISA was used to detect the HIF-1α level. The ELISA demonstrated that the cellulite group’s HIF-1α level was lower than the control group’s (5,742.39 ng/ml vs. 3,901.22 ng/ml) (Table 5).
When examining the relationship between
adiponectin and cellulite, we discovered that subjects with high serum HIF-1α have a 4.8 times higher chance of developing cellulite than those with a lower level of HIF-1α (p = 0.002, Table 6).
DISCUSSION
In postpubertal girls, cellulite is very common (85%–98%). This study found that most of the research subjects in the cellulite group were 26–33 years old (30%), while most of the control group were 18–25 years old (57.5%). In research conducted by Indriayani S, Putra IB, and Jusuf NK in Dermatology and Venereology Polyclinic, Universitas Sumatera Utara Hospital, the highest distribution of cellulite was found in women aged 20–30 years.8 The same condition was found in a study by Sadowski et al. of 40 cellulite patients ranging from 30–55 years old.9 This is also in accordance with research by Schunck et al. on 105 women ranging from 24–50 years old.10 Goldman stated that cellulite was prevalent in 85%–90% of women aged over 20 years.11 As we age, the quantity of collagen and elastin decreases, causing the dermis to become thinner and allowing fat to protrude into it. As people mature, their fat globules also become more hypertrophied. This explains why cellulite may appear more frequently as we age, but because cellulite can also affect young women, skin thickness changes brought on by aging are not the primary cause of cellulite.12
According to family history, this study found that most of the cellulite group had a family history from their mother consisting of 15 people (37.5%), and most of the control group had no family history, which consisted of 28 people (70%).
The clinical appearance and severity of cellulite are often similar between women in the same family due to the similarity in the distribution of subcutaneous fat.13 The Quebec Family Study states that there is a hereditary similarity in the distribution of subcutaneous fat by 42%.14 The thickness of the dermis (connective tissue), the thickness of the hypodermis (subcutaneous fat), the percentage of invagination of the hypodermis into the dermis, and the ratio of adipose tissue to connective tissue in the hypodermis all affect the severity of cellulite.15
By the characteristics of subjects based on BMI in this study, it was found that the majority of obese in the cellulite group were 19 people (47.5%), followed by overweight 13 people (32.5%), and normal was 8 people (20%). Most of the control group had a normal BMI of 26 people (65%). According to Mirrashed et al. and Hexsel et al., people with higher BMI have weaker and less dense connective tissue, which causes more adipose tissue lobules to protrude into the dermis. The dermis was also considerably thinner in cellulite-free areas.15,16 In accordance with the findings of Pierard GE, Nizet JL, and Pierard FC, and findings of Dobke et al.
states that the appearance of cellulite in individuals with normal BMI is related to an increase in the thickness of the fat lobule. Thus, it can be deduced that cellulite in women with average BMI is affected by the thickness of adipose tissue, which explains why these women typically experience less cellulite, and that cellulite in women with high BMI is affected by the quality of connective tissue.17,18
This is also in line with study findings by Lubis AF, Jusuf NK, and Putra IB, who found that while the waist-hip ratio (WHR) index can have an impact on cellulite, BMI increases do not cause it to rise. The waist-hip ratio (WHR) index is a predictor of abdominal obesity in both men and women. It is recommended as a measure of the additional distribution of body fat and a risk factor separate from BMI that is more potent. The result of the study showed that there was a positive correlation with a very strong level of strength between the WHR index and the Photonumeric Cellulite Severity Scale (PCSS) score, which is a validated objective method for measuring the degree of cellulite severity, which means the higher the value of the WHR index will be followed by the increasing PCSS score.19
We found that 2 individuals (5%) had cellulite on the femoral areas, 11 (27.5%) had it on the femoral, gluteus, and abdominal areas, and 27 (67.5%) subjects had it on the femoral and gluteus areas.
According to Stevens et al.’s study, 90% of cellulite cases were found on the thighs and buttocks.20 The same condition was found in a study by Indriayani S, Putra IB, and
Jusuf NK which cellulite most often occurs on the thighs and buttocks by 62.5%.8 However, this was different from Uebel et al. stated that the most cellulite locations were on thighs by 88.8%.21 According to one research, 95% of cellulite is found on the buttocks. The cosmetic (dimpled, peau d’orange) skin topographical changes that most frequently affect postpubertal women’s thighs, buttocks, and abdomen are known as cellulite. The region of the adipose distribution pattern, including the nape, breast, and upper arms, can also produce cellulite.22
The mean serum HIF-1α level in the cellulite group from our study was 5.74±2.39 and 3.90±1.22 in the control group. Until now, there has been no research on HIF-1α levels in cellulite patients. Research by Khalil et al. on HIF-1α levels in psoriasis patients was 3.38±1,87 and in the control group, was 1.0±0.0.23 Research by Wang et al. on HIF-1α levels in psoriasis patients was 1.19±0.12 and in the control group was 0.31±0.06.24 Research by Wu on HIF-1α levels in keloid patients was 2.73±0.35 and in the control group was 1.01±0.26.25 Due to associated variations in each study, this was different from our results. Other illnesses like cancer, high blood pressure, coronary heart disease, and diabetes mellitus can be impacted by factors influencing HIF-1 levels in the blood.7,26 In this study, all these things were excluded from the research subjects. In this study, there were 28 subjects (35%) with high HIF-1α levels in the cellulite group and 12 people (15%) with low HIF-1α levels in the cellulite group. The HIF-1α levels and cellulite have a statistically significant association, according to the Chi-square test. Cellulite risk increased by 4.8 times with high HIF-1α levels (p = 0.002).
Adipose tissue growth will raise HIF-1, which will in turn stimulate the fibrogenic response to cellulite.
Cellulite is also influenced by ischemia and oxygen. Chronic hypoxia results in microcirculatory disturbances, localized inflammation, endothelial failure, and subcutaneous fibrosis. HIF- 1 upregulation will result in local fibrosis and inflammation in adipose tissue.2 This is consistent with work by Emanuele et al., who discovered a strong connection
between cellulite and the HIF1 gene.
Cellulite is a result of adipose tissue fibrosis brought on by increased HIF1A mRNA. Adipose tissue had higher levels of HIF1A mRNA, which was favorably correlated with BMI. The HIF1A activity will be markedly reduced as a result of the rare mutant T allele of the rs11549465 polymorphism, and the frequency of the HIF1 T allele among women without cellulite will rise. Expression of this uncommon mutant T allele will result in a diminished fibroinflammatory reaction, which will lower the risk of cellulite and the development of subcutaneous septal fibrosis.3
The HIF-1α transcription factor, a heterodimer of the α and β components, will be encoded by the HIF1A gene.
Direct regulation of the α subunit by oxygen stress. Excessive caloric intake and increased adipose tissue deposition will cause decreasing in vascularity resulting in adipose tissue hypoxia and cause an increase in HIF-1α.3
Research by Halberg et al. in Denmark associated HIF-1α with fibrosis in adipose tissue in obese HIF-1α transgenic mice with controls, showing adipose tissue hypertrophy will cause hypoxia and increase HIF-1α.27 Hypoxia-inducible factor-1α will trigger an increase in the LOX enzyme, which triggers fibrosis so that increased expression of HIF-1α plays a role in the pathophysiology of cellulite.2
We acknowledge that there is a weakness in this study, in that we did not assess any confounding variables that might influence HIF-1α levels. Further research with a larger scale is needed to complete the shortcomings of this study.
CONCLUSION
Based on the entire study process conducted regarding the relationship between HIF-1 alpha levels and cellulite, it was concluded that there is a relationship between HIF-1 alpha levels and cellulite.
ACKNOWLEDGMENTS
We thank the Head of the Cosmetic Division Department of Dermatology and Venereology of the Faculty of Medicine, Universitas Sumatera Utara and Universitas Sumatera Utara Hospital.
CONFLICT OF INTEREST
The author declares no conflict of interest regarding the publication of this article.
FUNDING None.
ETHICAL CLEARANCE
The ethical clearance has been granted by Research Ethics Commission of Universitas Sumatera Utara.
AUTHOR CONTRIBUTIONS
All authors contributed equally to this study and the manuscript preparation until publication.
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