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Miyamoto K, Kondo S, Kondo T, Ishikawa R, Tani R, Inoue T, Matsunaga K, Minamino T, Kusaka T. Pathological features of non-alcoholic steatohepatitis in a pediatric patient with heterozygous familial hypobetalipoproteinemia: A case report. World J Hepatol 2025; 17:103299. [PMID: 40027560 PMCID: PMC11866159 DOI: 10.4254/wjh.v17.i2.103299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/26/2024] [Accepted: 01/21/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Heterozygous familial hypobetalipoproteinemia (FHBL) is a semi-autosomal disorder that is caused mainly by an APOB variant. It is usually asymptomatic and rarely leads to non-alcoholic steatohepatitis (NASH). CASE SUMMARY A 12-year-old boy was referred to our hospital after prolonged elevation of liver enzymes was observed during health checkups in Kagawa Prefecture. Abdominal ultrasound showed a bright liver, and laboratory investigations revealed low low-density lipoprotein cholesterol and apolipoprotein B protein levels. His family history included fatty liver and hypolipidemia in his father, which led to a clinical diagnosis of FHBL. A liver biopsy was performed on suspicion of liver fibrosis based on biomarkers. The liver tissue showed fatty steatosis, inflammation, hepatocyte ballooning, and fibrosis, indicating NASH. Genetic testing detected the APOB variant, and the patient was treated successfully with vitamin E. CONCLUSION It is important to assess family history and liver dysfunction severity in non-obese patients with hypolipidemia and fatty liver.
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Affiliation(s)
- Kiwako Miyamoto
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Miki 761-0793, Kagawa, Japan
| | - Sonoko Kondo
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Miki 761-0793, Kagawa, Japan.
| | - Takeo Kondo
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Miki 761-0793, Kagawa, Japan
| | - Ryou Ishikawa
- Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Miki 761-0793, Kagawa, Japan
| | - Ryosuke Tani
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Miki 761-0793, Kagawa, Japan
| | - Tomoko Inoue
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Miki 761-0793, Kagawa, Japan
| | - Keiji Matsunaga
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Miki 761-0793, Kagawa, Japan
| | - Tetsuo Minamino
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Miki 761-0793, Kagawa, Japan
| | - Takashi Kusaka
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Miki 761-0793, Kagawa, Japan
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Groselj U, Kafol J, Molk N, Sedej K, Mlinaric M, Sikonja J, Sustar U, Kern BC, Kovac J, Battelino T, Debeljak M. Prevalence, genetic variants, and clinical implications of hypocholesterolemia in children. Atherosclerosis 2025; 400:119065. [PMID: 39591895 DOI: 10.1016/j.atherosclerosis.2024.119065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/23/2024] [Accepted: 11/21/2024] [Indexed: 11/28/2024]
Abstract
BACKGROUND AND AIMS In contrast to extensively studied hypercholesterolemia, knowledge of hypocholesterolemia is limited. This study aims to assess the prevalence, clinical characteristics, and genetics of children and adolescents with hypocholesterolemia. METHODS This national prospective cross-sectional cohort study was part of Slovenia's universal opt-out cholesterol screening program. The first part assessed hypocholesterolemia prevalence among 3538 children aged 5 years, randomly selected at the mandatory check-up. The second part included analysis of demographic and clinical data and genetic testing of 71 individuals with suspected hypocholesterolemia (total cholesterol [TC] < 3.0 mmol/L [116.0 mg/dL]) referred to the Lipid Clinic of University Children's Hospital Ljubljana. RESULTS The prevalence of hypocholesterolemia among 3538 children was 2.66 % (95 % CI: 2.13-3.19 %). Among the 71 genetically tested individuals with suspected hypocholesterolemia, those with pathogenic variants had lower TC (2.58 ± 0.44 mmol/L vs. 2.85 ± 0.42 mmol/L [99.77 ± 17.02 mg/dL vs. 110.20 ± 16.24 mg/dL]; p = 0.037) and low-density lipoprotein cholesterol (1.00 ± 0.40 mmol/L vs. 1.33 ± 0.40 mmol/L [38.67 ± 15.47 mg/dL vs. 51.43 ± 15.47 mg/dL]; p = 0.014) compared to those without such variants. Genetic testing identified pathogenic alterations in 15 subjects, including 4 novel loss-of-function variants in the APOB gene. All but one subject were asymptomatic. CONCLUSIONS This study provides new clinical and genetic insights into hypocholesterolemia. Asymptomatic patients with hypocholesterolemia may not require further evaluation, but additional research is needed to understand hypocholesterolemia better.
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Affiliation(s)
- Urh Groselj
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Jan Kafol
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Neza Molk
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | | | - Matej Mlinaric
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Jaka Sikonja
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; Department of Endocrinology, Diabetes and Metabolic Diseases, Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Ursa Sustar
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia; Clinical Institute of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Barbara Cugalj Kern
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; Clinical Institute of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Jernej Kovac
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; Clinical Institute of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tadej Battelino
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Marusa Debeljak
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; Clinical Institute of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia.
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Wakabayashi T, Takahashi M, Okazaki H, Okazaki S, Yokote K, Tada H, Ogura M, Ishigaki Y, Yamashita S, Harada-Shiba M, on behalf of the Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of Health, Labour and Welfare of Japan. Current Diagnosis and Management of Familial Hypobetalipoproteinemia 1. J Atheroscler Thromb 2024; 31:1005-1023. [PMID: 38710625 PMCID: PMC11224688 DOI: 10.5551/jat.rv22018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 03/28/2024] [Indexed: 05/08/2024] Open
Abstract
Familial hypobetalipoproteinemia (FHBL) 1 is a rare genetic disorder with an autosomal codominant mode of inheritance and is caused by defects in the apolipoprotein (apo) B (APOB) gene that disable lipoprotein formation. ApoB proteins are required for the formation of very low-density lipoproteins (VLDLs), chylomicrons, and their metabolites. VLDLs transport cholesterol and triglycerides from the liver to the peripheral tissues, whereas chylomicrons transport absorbed lipids and fat-soluble vitamins from the intestine. Homozygous or compound heterozygotes of FHBL1 (HoFHBL1) are extremely rare, and defects in APOB impair VLDL and chylomicron secretion, which result in marked hypolipidemia with malabsorption of fat and fat-soluble vitamins, leading to various complications such as growth disorders, acanthocytosis, retinitis pigmentosa, and neuropathy. Heterozygotes of FHBL1 are relatively common and are generally asymptomatic, except for moderate hypolipidemia and possible hepatic steatosis. If left untreated, HoFHBL1 can cause severe complications and disabilities that are pathologically and phenotypically similar to abetalipoproteinemia (ABL) (an autosomal recessive disorder) caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene. Although HoFHBL1 and ABL cannot be distinguished from the clinical manifestations and laboratory findings of the proband, moderate hypolipidemia in first-degree relatives may help diagnose HoFHBL1. There is currently no specific treatment for HoFHBL1. Palliative therapy including high-dose fat-soluble vitamin supplementation may prevent or delay complications. Registry research on HoFHBL1 is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.
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Affiliation(s)
- Tetsuji Wakabayashi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
| | - Manabu Takahashi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
| | - Hiroaki Okazaki
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
| | - Sachiko Okazaki
- Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan
| | | | - Hayato Tada
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan
| | - Masatsune Ogura
- Department of Clinical Laboratory Technology, Faculty of Medical Science, Juntendo University, Tokyo, Japan
| | - Yasushi Ishigaki
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Shizuya Yamashita
- Department of Cardiology, Rinku General Medical Center, Osaka, Japan
| | - Mariko Harada-Shiba
- Cardiovascular Center, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - on behalf of the Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of Health, Labour and Welfare of Japan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
- Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan
- Chiba University, Chiba, Japan
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan
- Department of Clinical Laboratory Technology, Faculty of Medical Science, Juntendo University, Tokyo, Japan
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
- Department of Cardiology, Rinku General Medical Center, Osaka, Japan
- Cardiovascular Center, Osaka Medical and Pharmaceutical University, Osaka, Japan
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Han L, Wu L, Yin Q, Li L, Zheng X, Du S, Huang X, Bai L, Wang Y, Bian Y. A promising therapy for fatty liver disease: PCSK9 inhibitors. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155505. [PMID: 38547616 DOI: 10.1016/j.phymed.2024.155505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/30/2024] [Accepted: 02/28/2024] [Indexed: 05/01/2024]
Abstract
BACKGROUND Fatty liver disease (FLD) poses a significant global health concern worldwide, with its classification into nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) contingent upon the presence or absence of chronic and excessive alcohol consumption. The absence of specific therapeutic interventions tailored to FLD at various stages of the disease renders its treatment exceptionally arduous. Despite the fact that FLD and hyperlipidemia are intimately associated, there is still debate over how lipid-lowering medications affect FLD. Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) is a serine protease predominantly synthesized in the liver, which has a crucial impact on cholesterol homeostasis. Research has confirmed that PCSK9 inhibitors have prominent lipid-lowering properties and substantial clinical effectiveness, thereby justifying the need for additional exploration of their potential role in FLD. PURPOSE Through a comprehensive literature search, this review is to identify the relationship and related mechanisms between PCSK9, lipid metabolism and FLD. Additionally, it will assess the pharmacological mechanism and applicability of PCSK9 inhibitors (including naturally occurring PCSK9 inhibitors, such as conventional herbal medicines) for the treatment of FLD and serve as a guide for updating the treatment protocol for such conditions. METHODS A comprehensive literature search was conducted using several electronic databases, including Pubmed, Medline, Embase, CNKI, Wanfang database and ClinicalTrials.gov, from the inception of the database to 30 Jan 2024. Key words used in the literature search were "fatty liver", "hepatic steatosis", "PCSK9", "traditional Chinese medicine", "herb medicine", "botanical medicine", "clinical trial", "vivo", "vitro", linked with AND/OR. Most of the included studies were within five years. RESULTS PCSK9 participates in the regulation of circulating lipids via both LDLR dependent and independent pathways, and there is a potential association with de novo lipogenesis. Major clinical studies have demonstrated a positive correlation between circulating PCSK9 levels and the severity of NAFLD, with elevated levels of circulating PCSK9 observed in individuals exposed to chronic alcohol. Numerous studies have demonstrated the potential of PCSK9 inhibitors to ameliorate non-alcoholic steatohepatitis (NASH), potentially completely alleviate liver steatosis, and diminish liver impairment. In animal experiments, PCSK9 inhibitors have exhibited efficacy in alleviating alcoholic induced liver lipid accumulation and hepatitis. Traditional Chinese medicine such as berberine, curcumin, resveratrol, piceatannol, sauchinone, lupin, quercetin, salidroside, ginkgolide, tanshinone, lunasin, Capsella bursa-pastoris, gypenosides, and Morus alba leaves are the main natural PCS9 inhibitors. Excitingly, by inhibiting transcription, reducing secretion, direct targeting and other pathways, traditional Chinese medicine exert inhibitory effects on PCSK9, thereby exerting potential FLD therapeutic effects. CONCLUSION PCSK9 plays an important role in the development of FLD, and PCSK9 inhibitors have demonstrated beneficial effects on lipid regulation and FLD in both preclinical and clinical studies. In addition, some traditional Chinese medicines have improved the disease progression of FLD by inhibiting PCSK9 and anti-inflammatory and antioxidant effects. Consequently, the inhibition of PCSK9 appears to be a promising therapeutic strategy for FLD.
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Affiliation(s)
- Lizhu Han
- Department of Pharmacy, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Liuyun Wu
- Department of Pharmacy, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Qinan Yin
- Department of Pharmacy, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Lian Li
- Department of Pharmacy, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Xingyue Zheng
- Department of Pharmacy, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Shan Du
- Department of Pharmacy, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Xuefei Huang
- Department of Pharmacy, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Lan Bai
- Department of Pharmacy, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
| | - Yi Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu 610072, China.
| | - Yuan Bian
- Department of Pharmacy, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
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McHenry S, Awad A, Kozlitina J, Stitziel NO, Davidson NO. Low LDL Cholesterol Is Not an Independent Risk Factor for Hepatic Steatosis. Dig Dis Sci 2023; 68:3451-3457. [PMID: 37291473 DOI: 10.1007/s10620-023-07980-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 05/11/2023] [Indexed: 06/10/2023]
Abstract
BACKGROUND Genetic mutations causing defective VLDL secretion and low LDL cholesterol are associated with hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). AIMS Determine if low LDL cholesterol (< 5th percentile) was an independent predictor of hepatic steatosis. METHODS Secondary data analysis of the Dallas Heart study (an urban, multiethnic, probability-based sample), we defined hepatic steatosis utilizing intrahepatic triglyceride (IHTG) analyzed using magnetic resonance spectroscopy in conjunction and available demographic, serological and genetic information. We exclude patients on lipid lowering medications. RESULTS Of the 2094 subjects that met our exclusion criteria, 86 had a low LDL cholesterol, of whom 19 (22%) exhibited hepatic steatosis. After matching for age, sex, BMI, and alcohol consumption, low LDL cholesterol was not a risk factor for hepatic steatosis compared to those with normal (50-180 mg/dL) or high (> 180 mg/dL) LDL. When analyzed as a continuous variable, we observed lower IHTG in the low LDL group compared to the normal or high LDL groups (2.2%, 3.5%, 4.6%; all pairwise comparisons p < 0.001). Subjects with both hepatic steatosis and low LDL cholesterol exhibited a more favorable lipid profile but similar insulin resistance and hepatic fibrosis risk compared to other subjects with hepatic steatosis. The distribution of variant alleles associated with NAFLD, including PNPLA3, GCKR, and MTTP was indistinguishable between subjects with hepatic steatosis and low versus high LDL cholesterol. CONCLUSION These findings suggest that low serum LDL levels are not a useful predictor of hepatic steatosis and NAFLD. Moreover, subjects with low LDL exhibit a more favorable lipid profile and lower IHTG.
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Affiliation(s)
- Scott McHenry
- Division of Gastroenterology, Department of Medicine, Washington University in Saint Louis, St. Louis, MO, 53110, USA.
| | - Ameen Awad
- Division of Gastroenterology, Department of Medicine, Washington University in Saint Louis, St. Louis, MO, 53110, USA
| | - Julia Kozlitina
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Nathan O Stitziel
- Division of Gastroenterology, Department of Medicine, Washington University in Saint Louis, St. Louis, MO, 53110, USA
| | - Nicholas O Davidson
- Division of Gastroenterology, Department of Medicine, Washington University in Saint Louis, St. Louis, MO, 53110, USA
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Molk N, Bitenc M, Urlep D, Zerjav Tansek M, Bertok S, Trebusak Podkrajsek K, Sustar U, Kovac J, Battelino T, Debeljak M, Groselj U. Non-alcoholic fatty liver disease in a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant: a case report and systematic literature review. Front Med (Lausanne) 2023; 10:1106441. [PMID: 37384046 PMCID: PMC10293746 DOI: 10.3389/fmed.2023.1106441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 05/09/2023] [Indexed: 06/30/2023] Open
Abstract
Background Familial hypobetalipoproteinemia (FHBL) is an autosomal semi-dominant disorder usually caused by variants in the APOB gene that frequently interferes with protein length. Clinical manifestations include malabsorption, non-alcoholic fatty liver disease, low levels of lipid-soluble vitamins, and neurological, endocrine, and hematological dysfunction. Methods Genomic DNA was isolated from the blood samples of the pediatric patient with hypocholesterolemia and his parents and brother. Next-generation sequencing (NGS) was performed, and an expanded dyslipidemia panel was employed for genetic analysis. In addition, a systematic review of the literature on FHBL heterozygous patients was performed. Case report Genetic investigation revealed the presence of a heterozygous variant in the APOB (NM_000384.3) gene c.6624dup[=], which changes the open reading frame and leads to early termination of translation into the p.Leu2209IlefsTer5 protein (NP_000375.3). The identified variant was not previously reported. Familial segregation analysis confirmed the variant in the mother of the subject, who also has a low level of low-density lipoprotein and non-alcoholic fatty liver disease. We have introduced therapy that includes limiting fats in the diet and adding lipid-soluble vitamins E, A, K, and D and calcium carbonate. We reported 35 individuals with APOB gene variations linked to FHBL in the systematic review. Conclusion We have identified a novel pathogenic variant in the APOB gene causing FHBL in pediatric patients with hypocholesterolemia and fatty liver disease. This case illustrates the importance of genetic testing for dyslipidemias in patients with significant decreases in plasma cholesterol as we can avoid damaging neurological and ophthalmological effects by sufficient vitamin supplementation and regular follow-ups.
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Affiliation(s)
- Neza Molk
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Medical Center-University Children's Hospital, Ljubljana, Slovenia
| | - Mojca Bitenc
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Medical Center-University Children's Hospital, Ljubljana, Slovenia
| | - Darja Urlep
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital Ljubljana, University Medical Center, Ljubljana, Slovenia
| | - Mojca Zerjav Tansek
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Medical Center-University Children's Hospital, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Sara Bertok
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Medical Center-University Children's Hospital, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Katarina Trebusak Podkrajsek
- Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital Ljubljana, University Medical Center, Ljubljana, Slovenia
- Clinical Institute for Special Laboratory Diagnostics, University Children's Hospital, University Medical Center Ljubljana, Ljubljana, Slovenia
| | - Ursa Sustar
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Medical Center-University Children's Hospital, Ljubljana, Slovenia
- Clinical Institute for Special Laboratory Diagnostics, University Children's Hospital, University Medical Center Ljubljana, Ljubljana, Slovenia
| | - Jernej Kovac
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Clinical Institute for Special Laboratory Diagnostics, University Children's Hospital, University Medical Center Ljubljana, Ljubljana, Slovenia
| | - Tadej Battelino
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Medical Center-University Children's Hospital, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Marusa Debeljak
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Clinical Institute for Special Laboratory Diagnostics, University Children's Hospital, University Medical Center Ljubljana, Ljubljana, Slovenia
| | - Urh Groselj
- Department of Pediatric Endocrinology, Diabetes and Metabolism, University Medical Center-University Children's Hospital, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Momtazi-Borojeni AA, Banach M, Ruscica M, Sahebkar A. The role of PCSK9 in NAFLD/NASH and therapeutic implications of PCSK9 inhibition. Expert Rev Clin Pharmacol 2022; 15:1199-1208. [PMID: 36193738 DOI: 10.1080/17512433.2022.2132229] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION There are inconsistent findings regarding the effect of lipid-lowering agents on nonalcoholic fatty liver disease (NAFLD). Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is an important player in cholesterol homeostasis and intracellular lipogenesis, and PCSK9 inhibitors (PCSK9-i) have been found to be efficient for pharmacological management of hyperlipidemia. AREAS COVERED Whether PCSK9 (itself) or PCSK9-i affects NAFLD is still disputed. To address this question, we review published preclinical and clinical studies providing evidence for the role of PCSK9 in and the effect of PCSK9-I on the development and pathogenesis of NAFLD. EXPERT OPINION The current evidence from a landscape of preclinical and clinical studies examining the role of PCSK9 in NAFLD shows controversial results. Preclinical studies indicate that PCSK9 associates with NAFLD and nonalcoholic steatohepatitis (NASH) progression in opposite directions. In humans, it has been concluded that the severity of hepatic steatosis affects the correlation between circulating PCSK9 and liver fat content in humans, with a possible impact of circulating PCSK9 in the early stages of NAFLD, but not in the late stages. However, data from clinical trials with PCSK9-i reassure to the safety of these agents, although real-life long-term evidence is needed.
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Affiliation(s)
| | - Maciej Banach
- Department of Hypertension, Medical University of Lodz (MUL), Lodz, Poland.,Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Medicine, The University of Western Australia, Perth, Australia.,Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Grewal T, Buechler C. Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond. Int J Mol Sci 2022; 23:ijms23031070. [PMID: 35162992 PMCID: PMC8834914 DOI: 10.3390/ijms23031070] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/07/2022] [Accepted: 01/17/2022] [Indexed: 02/05/2023] Open
Abstract
Chronic liver diseases are commonly associated with dysregulated cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease of the proprotein convertase family that is mainly synthetized and secreted by the liver, and represents one of the key regulators of circulating low-density lipoprotein (LDL) cholesterol levels. Its ability to bind and induce LDL-receptor degradation, in particular in the liver, increases circulating LDL-cholesterol levels in the blood. Hence, inhibition of PCSK9 has become a very potent tool for the treatment of hypercholesterolemia. Besides PCSK9 limiting entry of LDL-derived cholesterol, affecting multiple cholesterol-related functions in cells, more recent studies have associated PCSK9 with various other cellular processes, including inflammation, fatty acid metabolism, cancerogenesis and visceral adiposity. It is increasingly becoming evident that additional roles for PCSK9 beyond cholesterol homeostasis are crucial for liver physiology in health and disease, often contributing to pathophysiology. This review will summarize studies analyzing circulating and hepatic PCSK9 levels in patients with chronic liver diseases. The factors affecting PCSK9 levels in the circulation and in hepatocytes, clinically relevant studies and the pathophysiological role of PCSK9 in chronic liver injury are discussed.
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Affiliation(s)
- Thomas Grewal
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia;
| | - Christa Buechler
- Department of Internal Medicine I, Regensburg University Hospital, 93053 Regensburg, Germany
- Correspondence:
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Welty FK. Familial hypobetalipoproteinemia and abetalipoproteinemia. CHOLESTEROL 2022:465-480. [DOI: 10.1016/b978-0-323-85857-1.00026-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Mahmoudi A, Butler AE, Jamialahmadi T, Sahebkar A. Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:3654660. [PMID: 34988225 PMCID: PMC8720586 DOI: 10.1155/2021/3654660] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/12/2021] [Accepted: 12/14/2021] [Indexed: 01/30/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of liver damage, affecting ~25% of the global population. NAFLD comprises a spectrum of liver pathologies, from hepatic steatosis to nonalcoholic steatohepatitis (NASH), and may progress to liver fibrosis and cirrhosis. The presence of NAFLD correlates with metabolic disorders such as hyperlipidemia, obesity, blood hypertension, cardiovascular, and insulin resistance. Fenofibrate is an agonist drug for peroxisome proliferator-activated receptor alpha (PPARα), used principally for treatment of hyperlipidemia. However, fenofibrate has recently been investigated in clinical trials for treatment of other metabolic disorders such as diabetes, cardiovascular disease, and NAFLD. The evidence to date indicates that fenofibrate could improve NAFLD. While PPARα is considered to be the main target of fenofibrate, fenofibrate may exert its effect through impact on other genes and pathways thereby alleviating, and possibly reversing, NAFLD. In this study, using bioinformatics tools and gene-drug, gene-diseases databases, we sought to explore possible targets, interactions, and pathways involved in fenofibrate and NAFLD. METHODS We first determined significant protein interactions with fenofibrate in the STITCH database with high confidence (0.7). Next, we investigated the identified proteins on curated targets in two databases, including the DisGeNET and DISEASES databases, to determine their association with NAFLD. We finally constructed a Venn diagram for these two collections (curated genes-NAFLD and fenofibrate-STITCH) to uncover possible primary targets of fenofibrate. Then, Gene Ontology (GO) and KEGG were analyzed to detect the significantly involved targets in molecular function, biological process, cellular component, and biological pathways. A P value < 0.01 was considered the cut-off criterion. We also estimated the specificity of targets with NAFLD by investigating them in disease-gene associations (STRING) and EnrichR (DisGeNET). Finally, we verified our findings in the scientific literature. RESULTS We constructed two collections, one with 80 protein-drug interactions and the other with 95 genes associated with NAFLD. Using the Venn diagram, we identified 11 significant targets including LEP, SIRT1, ADIPOQ, PPARA, SREBF1, LDLR, GSTP1, VLDLR, SCARB1, MMP1, and APOC3 and then evaluated their biological pathways. Based on Gene Ontology, most of the targets are involved in lipid metabolism, and KEGG enrichment pathways showed the PPAR signaling pathway, AMPK signaling pathway, and NAFLD as the most significant pathways. The interrogation of those targets on authentic disease databases showed they were more specific to both steatosis and steatohepatitis liver injury than to any other diseases in these databases. Finally, we identified three significant genes, APOC3, PPARA, and SREBF1, that showed robust drug interaction with fenofibrate. CONCLUSION Fenofibrate may exert its effect directly or indirectly, via modulation of several key targets and pathways, in the treatment of NAFLD.
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Affiliation(s)
- Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
| | | | - Tannaz Jamialahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Santos-Laso A, Gutiérrez-Larrañaga M, Alonso-Peña M, Medina JM, Iruzubieta P, Arias-Loste MT, López-Hoyos M, Crespo J. Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets. Biomedicines 2021; 10:biomedicines10010046. [PMID: 35052726 PMCID: PMC8773141 DOI: 10.3390/biomedicines10010046] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/23/2021] [Accepted: 12/23/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and type 2 diabetes mellitus, among other comorbidities. To date, only therapeutic strategies based on lifestyle changes have exhibited a beneficial impact on patients with NAFLD, but unfortunately this approach is often difficult to implement, and shows poor long-term adherence. For this reason, great efforts are being made to elucidate and integrate the underlying pathological molecular mechanism, and to identify novel and promising druggable targets for therapy. In this regard, a large number of clinical trials testing different potential compounds have been performed, albeit with no conclusive results yet. Importantly, many other clinical trials are currently underway with results expected in the near future. Here, we summarize the key aspects of NAFLD pathogenesis and therapeutic targets in this frequent disorder, highlighting the most recent advances in the field and future research directions.
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Affiliation(s)
- Alvaro Santos-Laso
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- Correspondence: (A.S.-L.); (J.C.)
| | - María Gutiérrez-Larrañaga
- Department of Immunology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.G.-L.); (M.L.-H.)
| | - Marta Alonso-Peña
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
| | - Juan M. Medina
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
| | - Paula Iruzubieta
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), 28029 Madrid, Spain
| | - María Teresa Arias-Loste
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), 28029 Madrid, Spain
| | - Marcos López-Hoyos
- Department of Immunology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.G.-L.); (M.L.-H.)
| | - Javier Crespo
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute (IDIVAL), 39008 Santander, Spain; (M.A.-P.); (J.M.M.); (P.I.); (M.T.A.-L.)
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), 28029 Madrid, Spain
- Correspondence: (A.S.-L.); (J.C.)
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