Human Hepatocyte Nuclear Factors (HNF1 and LXRb) Regulates CYP7A1 in HIV-Infected Black South African Women with Gallstone Disease: A Preliminary Study

Abstract Background: Female sex, high estrogen levels, aging, obesity and dyslipidemia are some of the risk factors associated with gallstone formation. HIV infected patients on combination antiretroviral therapy (cART) are more prone to hypercholesterolemia. Bile acid synthesis is initiated by cholesterol 7-alpha hydroxylase (CYP7A1) and regulated by hepatocyte nuclear factors (HNF1α, HNF4α and LXRb).Aim/ Objective: To evaluate the expression of HNF1α, HNF4α, LXRb and miRNAs (HNF4α specific: miR-194-5p and miR-122*_1) that regulate CYP7A1 transcription in HIV-infected Black South African women on cART and presenting with gallstones relative to HIV negative patients with gallstone disease. Methods: Females (n = 96) presenting with gallstone disease were stratified based on HIV status. The gene expression of CYP7A1, HNF1α, HNF4α, LXRb, miR-194-5p and miR-122*_1 was determined using RT-qPCR. Messenger RNA and miRNA levels were reported as fold change expressed as 2-ΔΔCt (RQ min; RQ max). Fold changes >2 and <0.5 were considered significant. Results: HIV-infected females were older in age (p = 0.0267) and displayed higher low-density lipoprotein cholesterol (LDL-c) (p = 0.0419), CYP7A1 [2.078-fold (RQ min: 1.278; RQ max: 3.381)], LXRb [2.595-fold (RQ min: 2.001; RQ max: 3.000)] and HNF1α [3.428 (RQ min: 1.806; RQ max: 6.507] levels. HNF4α [0.642-fold (RQ min: 0.266; RQ max: 1.55)], miR-194-5p [0.527-fold (RQ min: 0.37; RQ max: 0.752)] and miR-122*_1 [0.595-fold (RQ min: 0.332; RQ max: 1.066)] levels were lower in HIV-infected females. Conclusions: HIV-infected women with gallstone disease displayed higher LDL-c levels and increased bile acid synthesis which was evident by the elevated expression of CYP7A1, HNF1α and LXRb. This could have been further influenced by cART and aging.

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Symptomatic gallstones and HIV in black South African women: Changing trends of gallstone disease?

Southern African Journal of HIV Medicine ◽

10.4102/sajhivmed.v22i1.1208 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Suman Mewa Kinoo ◽

Savania Nagiah ◽

Anil Chuturgoon ◽

Bhugwan Singh

Keyword(s):

Risk Factors ◽

South African ◽

Statistical Tests ◽

Gallstone Disease ◽

African Women ◽

Categorical Variables ◽

Weight Category ◽

Black South African ◽

Case Series Study ◽

South African Women

Background: The incidence of metabolic disorders in human immunodeficiency virus (HIV) endemic settings is a prevailing burden in developing countries. Cholesterol homeostasis and fat metabolism are altered by HIV and antiretroviral therapy (ART), thereby possibly contributing to complications such as gallstone formation.Objectives: The aim of this study was to evaluate established risk factors for the formation of cholesterol gallstones in black South African women living with HIV (WLHIV).Method: A case series study was conducted of all black South African women undergoing cholecystectomy for gallstone disease over a 1-year period at King Edward VIII Hospital, Durban, South Africa. Age, body mass index (BMI), family history of gallstones, oestrogen exposure and lipograms were compared between WLHIV and uninfected women. Categorical variables were tested using either the Fisher’s exact test or Pearson’s chi-square test. Means were compared using independent t-tests. For non-normally distributed data, the Mann–Whitney U test was used. Statistical tests were two-sided, and p-values of less than 0.05 were considered statistically significant.Results: A total of 52 patients were assessed, 34 HIV-uninfected and 18 WLHIV. The median age of WLHIV versus the uninfected women was 35 and 50 years, respectively, (p = 0.015). A statistically significant number of uninfected women were in the overweight/obese category (BMI 25 kg/m2) compared to the normal weight category (BMI 25 kg/m2) (p 0.001). The number of obese WLHIV did not reach statistical significance.Conclusion: The age of occurrence of gallstone disease amongst black South African WLHIV was significantly lower and fewer women were obese compared with the uninfected women with gallstone disease. These findings differ from known gallstone risk factors in other populations and in uninfected black South African women. This could be attributed to the metabolic alterations caused by HIV infection itself and/or to the long-term use of ART. Larger cohort studies are required to elucidate the role of HIV and ART in cholestatic disease.

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