Peroxisome proliferator-activated receptor gamma mutation in familial partial lipodystrophy type three: A case report and review of literature

Abstract

BACKGROUND

Familial partial lipodystrophy disease (FPLD) is a collection of rare genetic diseases featuring partial loss of adipose tissue. However, metabolic difficulties, such as severe insulin resistance, diabetes, hypertriglyceridemia, and hypertension frequently occur alongside adipose tissue loss, making it susceptible to misdiagnosis and delaying effective treatment. Numerous genes are implicated in the occurrence of FPLD, and genetic testing has been for conditions linked to single gene mutation related to FPLD. Reviewing recent reports, treatment of the disease is limited to preventing and improving complications in patients.

CASE SUMMARY

In 2017, a 31-year-old woman with diabetes, hypertension and hypertriglyceridemia was hospitalized. We identified a mutation in her peroxisome proliferator-activated receptor gamma (PPARG) gene, Y151C (p.Tyr151Cys), which results in a nucleotide substitution residue 452 in the DNA-binding domain (DBD) of PPARG. The unaffected family member did not carry this mutation. Pioglitazone, a PPARG agonist, improved the patient’s responsiveness to hypoglycemic and antihypertensive therapy. After one year of treatment in our hospital, the fasting blood glucose and glycosylated hemoglobin of the patient were close to normal.

CONCLUSION

We report a rare PPARG mutation, Y151C, which is located in the DBD of PPARG and leads to FPLD, and the preferred agent is PPARG agonists. We then summarized clinical phenotypic characteristics of FPLD3 caused by PPARG gene mutations, and clarified the relationship between different mutations of PPARG gene and the clinical manifestations of this type of FPLD. Additionally, current treatments for FPLD caused by PPARG mutations are reviewed.

Key Words: Familial partial lipodystrophy; Peroxisome proliferator-activated receptor gamma; Tyr151Cys; Phenotypic heterogeneity; Case report

Core Tip: This study reports a rare peroxisome proliferator-activated receptor gamma (PPARG) mutation (Y151C) in a 31-year-old woman with familial partial lipodystrophy type 3 (FPLD3), characterized by adipose tissue loss and metabolic complications. The mutation was identified in the PPARG DNA-binding domain. Pioglitazone, a PPARG agonist, effectively improved the patient’s glycemic and blood pressure control. This highlights the importance of genetic testing in FPLD3 diagnosis and the potential of PPARG agonists in managing metabolic complications.

INTRODUCTION

Lipodystrophy syndrome is a rare congenital or acquired disease that results in partial or systemic loss of adipose tissue[1]. The condition could be a congenital manifestation of genetic mutations or acquired as a result of autoimmune disorders or highly active antiretroviral therapy[2-4]. It may be systemic, affecting the entire body, or localized to certain body parts. Four primary types are recognized within the classification of lipodystrophy: Congenital systemic lipodystrophy, familial partial lipodystrophy (FPL), acquired systemic lipodystrophy, and acquired local lipodystrophy[5,6]. The pertinent knowledge regarding FPL disease (FPLD) will be presented below.

FPLD comprises a set of autosomal dominant inherited diseases that feature a reduction of fat in the arms, legs, and glutes[7]. Patients with varying clinical phenotypic features have led to the classification of FPLD into several subtypes, namely FPLD1 through FPLD6[1]. The classification of FPL into different types is primarily attributed to its genetic heterogeneity, variations in clinical manifestations, genetic patterns, and familial aggregation. For instance, FPLD2 is associated with missense mutations in the LMNA gene, whereas FPLD3 is linked to missense mutations in the gene encoding peroxisome proliferator-activated receptor gamma (PPARG). Specifically, FPLD1 is characterized by the complete loss of fat in the limbs, with no involvement of trunk and facial fat; FPLD2 manifests as normal condition during childhood, followed by progressive and symmetrical loss of subcutaneous fat in the limbs, accompanied by compensatory excess fat accumulation in the upper part of the head, face, neck, and clavicle; FPLD3 may present with lipoatrophy similar to FPLD2, but with a later onset and milder symptoms[8,9]. Numerous genes are related to the occurrence of FPLD, for example, the single gene mutation of more than 10 genes such as LMNA gene is closely related to the occurrence of FPLD[1]. Among them, mutations of PPARG gene are particularly associated with FPLD3[10]. We report a rare PPARG mutation, which leads to partial lipodystrophy, insulin resistance, diabetes, hypertriglyceridemia and hypertension. The functionally abnormal protein can be stimulated by rosiglitazone.

CASE PRESENTATION

Chief complaints

A 31-year-old woman was referred to our hospital in November 2017 due to polydipsia, polyuria, and more food and weight loss for 2 years.

History of present illness

Polydipsia, polyuria, and more food and weight loss for 2 years.

Personal and family history

As to her family medical history, her father and grandmother was diagnosed with “Diabetes, hypertension and hypertriglyceridemia”. The family contained 3 generations of diabetics. A total of 5 peoples have been diagnosed with diabetes or impaired glucose tolerance.

Physical examination

She was 162 cm tall, weighed 53 kg, and the body mass index (BMI) was 20.19 kg/m². Her blood pressure was 160/118 mmHg.

Laboratory examinations

Liver function: Total bilirubin: 25.20 mmol/L; Direct bilirubin: 6.38 mmol/L; Indirect bilirubin: 18.60 μmol/L; Triglyceride (TG): 4.00 mmol/L; Total cholesterol: 3.85 mmol/L; Low-density lipoprotein cholesterol: 2.57 mmol/L; High-density lipoprotein-cholesterol: 0.61 mmol/L; Fasting blood glucose: 9.95 mmol/L; Glycosylated hemoglobin (HbA1c): 10.20%. Insulin release test and C-peptide release test: Pre-meal insulin: 16.47 μIU/mL; 1 hour post-meal insulin: 30.15 μIU/mL; 2 hours post-meal insulin: 37.30 μIU/mL; 3 hours post-meal insulin: 27.24 μIU/mL; pre-meal C-peptide: 1.30 ng/mL; 1 hour post-meal C-peptide: 2.09 ng/mL; 2 hours post-meal: 3.27 ng/mL; 3 hours post-meal: 3.28 ng/mL. Diabetes autoantibodies (glutamate decarboxylase, insulin antibodies, and pancreatic islet cell antibodies) were negative. Ultrasound indicates abnormal cardiac diastolic function and fatty liver. The fundus examination indicates retinal detachment and bleeding, and the fundal vessels were unremarkable. Neuroelectromyography was normal. Renal function normal and 24 hours urinary protein is 65 mg/24 hours.

Imaging examinations

No imaging examinations were performed.

FINAL DIAGNOSIS

FPLD3.

TREATMENT

The patient was given insulin, fenofibrate, irbesartan and levamlodipine besylate (Table 1) with diet and exercise therapy.

Table 1 Comparison of treatment regimens before and after the use of PPARG agonists.

Before pioglitazone treatment	After pioglitazone treatment
Insulin glargine injection, 12 μL, QD	Pioglitazone, 30 mg, QD
Recombinant lispro insulin injection, 10 μL, TID	Dapagliflozin, 10 mg, QD
Fenofibrate, 200 mg, QD	Fenofibrate, 200 mg, QD
Irbesartan, 300 mg/day, QD	Irbesartan, 150 mg, QD
Levamlodipine besylate, 2.5 mg/day, QD

QD: Once daily; TID: Three times daily.

OUTCOME AND FOLLOW-UP

Considering that the patient is relatively young and exhibits multiple symptoms of metabolic disorders, as well as having a family history of three generations with consecutive occurrences, the patient and her parents underwent genetic testing. Whole exome sequencing revealed a heterozygous pathogenic mutation Y151C (c.452A > c.452G) in exon 3 of the PPARG gene in the proband and her father, which led to the diagnosis of FPLD. Sanger sequencing had not found the same mutation in her mother (Figure 1). The patient was given pioglitazone after being diagnosed with FPLD, with significant reductions in the types and dosages of other medications used (Table 1). One year later, she was 73 kg with BMI 26.30 kg/m². Fasting blood glucose was 7.2 mmol/L and HbA1c was 6.8%, blood pressure was 160/118 mmHg, TG was 4.00 mmol/L.

Figure 1  DNA sequencing profiles of the proband and her parents and national center for biotechnology information reference sequences.

DISCUSSION

FPLD3

Referencing the previous text, it is believed that FPL of the third subtype [FPLD3; online mendelian inheritance in man (OMIM) 604367], an autosomal dominant genetic condition, arises from a prevailing non-functional mutation within the PPARG gene[11]. People affected by FPLD3 possess and retain a normal fat distribution pattern during their early childhood; however, as they enter their teen years, they undergo a decrease in the fatty layer beneath the skin in their arms and legs, as well as in specific areas of their torso, creating the appearance of enhanced muscular development. Typically, people exhibit a shortage of subcutaneous fat in their arms and legs as well as their glutes, but they preserve both subcutaneous and visceral fat in the region of their midsection. Furthermore, fat irregularly accumulates in the liver and muscles, giving rise to numerous metabolic disorders including insulin resistance, non-alcoholic fatty liver disease, abnormal blood lipid levels, and type 2 diabetes mellitus, among other conditions[1]. Furthermore, FPLD3 tends to impact female patients with greater frequency and severity compared to male counterparts. Affected females frequently develop features of polycystic ovarian syndrome including polycystic ovaries, hirsutism, and oligomenorrhea[12]. Early onset of cardiovascular disease has also been reported[5].

Structure and function of PPARG and its expression

PPARG, a member of the family of peroxisome proliferator-activated receptors which also includes PPAR-α, PPAR-β, and PPAR-δ among others, is a type of PPAR. PPARG belongs to the vast family of nuclear hormone receptors[13], which includes 48 transcription factors specific to humans. Steroids, thyroid hormones, vitamins, lipid metabolites, and all obiotin exert control by specifically attaching themselves, thereby regulating these elements[14,15]. Activators of peroxisome proliferators attach themselves to compounds that stimulate the multiplication of peroxisomes[16]. The cellular peroxidase organelle facilitates the oxidative breakdown of fatty acids (OMIM 601487), while PPARG, which is produced by the PPARG gene, plays a role in managing fat synthesis and the preservation of adipose tissue[13]. The primary expression of this is observed in fat tissue, particularly within the cells of both white and brown fat[17-20]. The expression of PPARG is more pronounced in monocytes (or macrophages) and colonic regions of adipose tissue, whereas it is less abundant in various additional tissues. The mechanism by which it governs the transcription of specific genes is triggered by a variety of endogenous lipid compounds. Nonetheless, a definitive principal natural ligand remains to be distinctly recognized[15].

PPARG is comprised of four distinct regions with specific roles: These include the activation function 1 domain, DNA binding domain, hinge domain, and ligand binding domain[21]. PPARG1 and PPARG2, which are subtypes of PPARG, exhibit variations at their N-termini; specifically, PPARG2 possesses an additional 30 amino acids compared to PPARG1. These subtypes are derived from different transcription initiation sites; the PPARG gene has nine exons, eight of which encode PPARG1 and seven of which encode PPARG2. G1 and G2 are mainly expressed in adipocytes, while PPAR-G1 is also expressed at lower levels in other tissues, including macrophages, liver, brain, and muscle[22].

PPARG is crucial for the differentiation of adipocytes, metabolic processes, insulin responsiveness, and managing inflammation, due to its wide range of functions[23]. PPARG plays a pivotal role in preadipocyte differentiation into mature adipocytes by binding with retinoid X receptor, a member of the nuclear receptor family, to form a heterodimer, which regulates adipocyte differentiation, lipid storage, and release[15,24,25]. PPARG, an important modulator of adipogenesis and adipose tissue homeostasis, exhibits high expression levels in both white and brown fat tissues, as well as in additional tissue types. It promotes fat production without enlarging fat cells; instead, it leads to an increase in the number of smaller cells. Furthermore, its function includes promoting the transformation of subcutaneous fat into visceral fat[1].

Clinical phenotype of FPLD3 due to PPARG mutations

The PPARG gene is essential for the transformation and metabolic processes of fat cells, significantly affecting the clinical manifestations associated with atypical alterations in human fat tissue[26]. In this section, we will provide a brief introduction to the clinical phenotype of FPLD patients with PPARG gene mutations. Additionally, we will summarize the clinical phenotype of FPLD patients with mutations at different sites in the PPARG gene. By doing so, we hope to enhance our understanding of FPLD caused by PPARG mutation and facilitate clinical diagnosis and treatment.

Present-day scholarly articles suggest that divergent mutations at various locations within an identical gene may lead to unique clinical manifestations, a concept referred to as “phenotypic heterogeneity” in the field of genetics. We have compiled clinical phenotype information and PPARG mutation types for FPLD patients diagnosed with PPARG gene mutations, as shown in Table 2. We discovered that patients with FPLD caused by PPARG mutations may experience metabolic syndromes, including diabetes (or insulin resistance), hypertriglyceridemia, hypertension, and other cardiovascular diseases, in addition to lipid dystrophy. Lipodystrophy is considered the predominant clinical phenotype associated with mutations in the PPARG gene, particularly in contrast to diabetes, even though there are reports of diabetes also occurring due to specific mutations in the PPARG gene[27,28]. This is justified by the fact that the PPARG gene substantially regulates adipocyte differentiation and metabolism[29-31]. Therefore, the most direct effect arising from its mutation should be disturbance of lipid metabolism. Ectopic fat accumulation often results in local lipodystrophy among patients. The occurrence of metabolic disorders, such as diabetes, is likely part of a series of metabolic disorder syndromes secondary to or accompanied by abnormal lipid metabolism. This is due to the harmful impact of ectopic fat accumulation on normal tissues and cells, as previously mentioned.

Table 2 Summary of clinical phenotypic characteristics of familial partial lipodystrophy disease caused by PPARG mutation[11,16,24,26,34-39,42,50-62].

Domain	Gene mutation type	Manifestation				Ref.
		Diabetes/insulin resistance	Hypertrigly-ceridemia	Hyper-tension	Others
LBD	H449L	Yes	Yes		PCOS, acanthosis nigricans, hepatocyte steatosis, no coronary arteries and other vascular diseases	Demir et al[34]
	P467L	Yes	Yes	Yes	Cirrhosis and liver cancer develop in the context of non-alcoholic steatohepatitis	Savage et al[24]; Barroso et al[35]
	V290M	Yes	Yes	Yes	Primary amenorrhea, hypertrichosis, acanthosis nigricans	Savage et al[24]; Barroso et al[35]
	F310S	Yes	Yes		Fatty liver, liver dysfunction, albuminuria and diabetic peripheral neuropathy	Chen et al[36]
	F162C	Yes	Yes		Hepatomegaly, metabolic steatohepatitis	Melzer et al[38]
	R425C	Yes	Yes		Lipodystrophy of the extremities and face, hirsutism	Agarwal and Garg[39]
	Q157G	Yes	Yes	Yes	Polycystic ovarian syndrome, premature menopause at the age of 38, underwent hysterectomy due to fibroids at the age of 54, osteoporosis at the age of 58	Lambadiari et al[42]
	A261E	Yes	Yes		PCOS, lipodystrophy of the extremities	Agostini et al[16]
	R308P	Yes	Yes		PCOS, Nonalcoholic fatty liver disease	Agostini et al[16]; Majithia et al[50]
	K347T	Yes	Yes	Yes	Lipoatrophy of the limbs, elevated creatine kinase levels, recurrent pancreatitis	Miehle et al[51]
	E352Q	Yes	Yes		Low level of plasma leptin, hepatic steatosis, whereas funduscopy was normal	Castell et al[52]
	Y355X	Yes	Yes	Yes	Steatosis hepatis, Family history of similar physical appearance, acute pancreatitis	Francis et al[53]
	T356R	Yes	Yes		Non-alcoholic fatty liver, dyslipidemia, and low serum adiponectin levels	Majithia et al[50]
	R385X	Yes	Yes	Yes	Acanthosis nigricans, lipodystrophy affecting gluteal, pancreatitis, cutaneous eruptive xanthomata	Agostini et al[54]
	P387S	Yes	Yes		Severe insulin resistance, non-alcoholic fatty liver, dyslipidemia, and low serum adiponectin levels	Majithia et al[50]
	F388L	Yes	Yes		Polycystic ovarian disease, atrophy of gluteal fat	Hegele et al[11]
	A417V	Yes	Yes		Severe insulin resistance, non-alcoholic fatty liver, dyslipidemia, and low serum adiponectin levels	Majithia et al[50]
	D424N		Yes	Yes	Muscular hypertrophy was observed on the legs, slight acanthosis nigricans was present on the neck, axillae and inguinal folds, loss of subcutaneous fat from the arms, accumulation of subcutaneous fat was present in face, chin, trunk and abdomen, ovarian cyst	Lüdtke et al[55]
	L451P	Yes	Yes		Hirsutism, marked loss of subcutaneous fat from the extremities but truncal fat was slightly increased	Broekema et al[56]
	H477L	Yes	Yes		Trunk-sparing lipodystrophy, acanthosis nigricans, multiple acrochordons, an excess of subcutaneous adipose tissue in the abdomen with a decreased amount of subcutaneous adipose tissue in the patient’s lower extremities	Akinci et al[57]
	P495L	Yes	Yes		Severe insulin resistance, non-alcoholic fatty liver, dyslipidemia, and low serum adiponectin levels	Barroso et al[35]
DBD	Y151C	Yes	Yes	Yes	Pancreatitis, cardiovascular disease, no acanthosis nigricans or hirsutism	Visser et al[37]
	FS138X	Yes			Bilateral cataracts, bilateral hearing impairment and peripheral neuropathy	Hegele et al[58]
	C114R	Yes	Yes	Yes	PCOS, hepatic steatosis	Agostini et al[54]
	E157D	Yes	Yes		Hepatic steatosis, acanthosis nigricans, hirsutism, PCOS	Campeau et al[59]
	C131Y	Yes	Yes	Yes	PCOS, hepatic steatosis	Agostini et al[54]
	G161V	Yes	Yes	Yes	Bilateral fallopian tube obstruction, eruptive xanthoma, type V dyslipidemia, pancreatitis, severe hepatic steatosis	Lau et al[26]
	R165T	Yes	Yes	Yes	Peripheral lipoatrophy, muscular hypertrophy, liver steatosis	Auclair et al[60]
	FS186X	Yes	Yes	Yes	Acanthosis nigricans	Savage et al[61]
	C162W	Yes	Yes	Yes	PCOS, hepatic steatosis	Agostini et al[54]
	R194W	Yes	Yes	Yes	PCOS, acanthosis nigricans	Monajemi et al[62]

LBD: Ligand-binding domain; DBD: DNA binding domain; PCOS: Polycystic ovarian syndrome.

Treatment

Based on current reports, treatments for lipodystrophy are limited to preventing and improving patients’ metabolic complications and cannot achieve a complete cure or radical treatment. Consequently, this part will scrutinize contemporary studies addressing FPLD therapies linked to PPARG mutations, with a focus on three key domains: Overall management strategies, interventions for insulin resistance and diabetes mellitus, and remedies for lipodystrophy.

Dietary control and moderate exercise are the cornerstones of the treatment of all types of lipodystrophy, as this is not only beneficial for lipodystrophy itself, but also helps to ameliorate metabolic disorders such as diabetes mellitus and hypertriglyceridemia, as well as to reduce the risk of coronary atherosclerotic heart disease[6]. Individuals undergoing treatment are advised to adhere to a nutritional regimen comprising 50%-60% carbs, 20%-30% fats, and roughly 20% protein[6,32]. Since some patients with FPLD have hyperphagia due to reduced leptin levels[7], they should be advised to adopt an energy-restricted diet, as overeating is likely to precipitate or exacerbate their metabolic complications and lead to disease progression. In the absence of specific contraindications, most patients should engage in physical activity, but those with cardiac disease should undergo a cardiac evaluation prior to initiating exercise therapy while avoiding strenuous exercise[6].

As with all patients with type 2 diabetes mellitus, improvement of glycemia and insulin resistance will have multiple beneficial metabolic effects, including improved TG levels[33]. Metformin and thiazolidinediones (TZDs) have shown efficacy in the management of diabetes in patients with lipodystrophies[34-39]. An open label study of troglitazone, a TZD, on patients with lipodystrophy showed an improvement in metabolic profile, including HbA1c and fasting TG[39]. Troglitazone is no longer available due to hepatic toxicity[40,41], and evidence is limited for other TZDs. In our case, pioglitazone significantly improved insulin resistance, reduced insulin dosage, and helped with blood pressure and serum lipids. Some case studies using pioglitazone in FPLD patients have shown improvement in dysglycemia and dyslipidemia[36-38]. However, pioglitazone has been associated with an increased incidence of heart failure and fluid retention, so it is generally used with caution[42]. Insulin is also used in the management of diabetes, although increased doses and concentrated preparations of insulin may be required in some lipodystrophy patients with severe insulin resistance[43]. Additional treatments for high blood sugar, such as inhibitors of sodium-glucose cotransporter 2 and agonists for glucagon-like peptide-1 receptors, are utilized for lipodystrophy conditions. However, clinical trials targeting these groups are lacking, even though some animal research and individual case studies suggest they may be effective[44-46].

Metreleptin, a recombinant human leptin analogue, represents leptin replacement therapy and is currently the only effective therapeutic agent for lipodystrophy. The regulatory authorities in the United States, European Union, and Japan have sanctioned the use of metreleptin as a therapeutic option for lipodystrophy[47]. Of note, metreleptin is not currently food and drug administration-approved for use in patients with FPLD and is only available through trials, compassionate use, or special access programs or, to a lesser extent, in Japan[6]. Practice recommendations from various medical societies propose that for patients with partial lipodystrophy who demonstrate leptin deficiency (leptin < 4 ng/mL) and significant metabolic complications (HbA1c > 8% and/or TG > 500mg/dL), Metreleptin could be considered a viable treatment alternative[6]. Based on the lastest reports, the efficacy of metriptyline in patients with lipodystrophy in the pathogenic variant of PPARG, mainly in terms of improvement in serum TG and glycemic parameters (e.g., HbA1c), is controversial, as the improvement in hypertriglyceridemia was not significant in some reported cases[33,48,49].

CONCLUSION

We reported a rare case of FPLD3 caused by a rare PPARG mutation Y151C. In addition, we reviewed the current understanding of FPLD3 and PPARG gene, including the typical clinical manifestations of FPLD3, the structure, function and expression of PPARG gene, etc. By reviewing previous literature reports, we summarized some clinical phenotypes of FLPD3 caused by PPARG gene mutations in the form of tables. It is not difficult to find that different mutations in the same gene have different clinical phenotypes, that is, clinical phenotype heterogeneity, and the same mutation in the same gene has different clinical phenotypes. Finally, we review current treatments for this disease, including general treatments such as diet and exercise, measures to control blood glucose and improve insulin sensitivity in type 2 diabetes, and leptin, the only effective treatment for lipodystrophy at present. We earnestly anticipate that the revelations from our paper will offer groundbreaking perspectives, ultimately catalyzing the development of innovative therapeutic approaches for FPL and improving patient well-being.