ABSTRACT
Elevated circulating dipeptidyl peptidase-4 (DPP4) is a biomarker for liver disease, but its involvement in gluconeogenesis and metabolic associated fatty liver disease progression remains unclear. Here, we identified that DPP4 in hepatocytes but not TEK receptor tyrosine kinase-positive endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4-/-) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of Dpp4-/- mice displayed enrichment for inflammasome, p53, and senescence programs compared with littermate controls. High-fat, high-cholesterol feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling. Moreover, in a lean mouse model of severe nonalcoholic fatty liver disease, phosphatidylethanolamine N-methyltransferase mice, we observed a 4-fold increase in circulating DPP4, in contrast with previous findings connecting DPP4 release and obesity. Last, we evaluated DPP4 levels in patients with hepatitis C infection with dysglycemia (Homeostatic Model Assessment of Insulin Resistance > 2) who underwent direct antiviral treatment (with/without ribavirin). DPP4 protein levels decreased with viral clearance; DPP4 activity levels were reduced at long-term follow-up in ribavirin-treated patients; but metabolic factors did not improve. These data suggest elevations in DPP4 during hepatitis C infection are not primarily regulated by metabolic disturbances.
Subject(s)
Hepatitis C , Non-alcoholic Fatty Liver Disease , Mice , Animals , Non-alcoholic Fatty Liver Disease/metabolism , Glucose/metabolism , Glucagon-Like Peptide 1/metabolism , Dipeptidyl Peptidase 4/metabolism , Endothelial Cells/metabolism , Ribavirin/metabolism , Hepatocytes/metabolismABSTRACT
Patients with homozygous familial hypercholesterolemia (HoFH) have extremely elevated levels of low-density lipoprotein cholesterol (LDL-C), with premature atherosclerosis and aortic valve disease. Available drug treatments are inadequate, and even with serial apheresis, HoFH patients rarely achieve acceptable LDL-C levels. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 that lowers LDL-C via a novel receptor-independent mechanism. We describe an Ontario patient with HoFH who for 17 months has been treated with monthly infusions of evinacumab added to pre-existing statin, ezetimibe, and evolocumab therapy. Evinacumab in this HoFH patient was associated with markedly improved LDL-C levels and decreased frequency of apheresis.
Les patients atteints d'hypercholestérolémie familiale homozygote (HFH) présentent des taux extrêmement élevés de cholestérol à li-poprotéines de faible densité (C-LDL) avec une athérosclérose prématurée et une valvulopathie aortique. Les traitements médicamenteux disponibles sont inadéquats et, même avec un traitement par aphérèses en série, on obtient rarement des taux acceptables de C-LDL chez les patients atteints d'HFH. L'évinacumab, un anticorps monoclonal dirigé contre la protéine 3 de type angiopoïétine, réduit le taux de C-LDL par un nouveau mécanisme indépendant du récepteur. Nous décrivons le cas d'un patient ontarien atteint d'HFH traité par l'évinacumab pendant 17 mois à raison d'une perfusion mensuelle administrée en complément d'un traitement préexistant par une statine, l'ézétimibe et l'évolocumab. L'évinacumab a été associé chez ce patient à une amélioration marquée des taux de C-LDL et à une diminution de la fréquence des aphérèses.
ABSTRACT
PURPOSE OF REVIEW: Amyloidosis is caused by the deposition of misfolded aggregated proteins called amyloid fibrils that in turn cause organ damage and dysfunction. In this review, we aim to summarize the genetic, clinical, and histological findings in apolipoprotein-associated hereditary amyloidosis and the growing list of mutations and apolipoproteins associated with this disorder. We also endeavor to summarize the features of apolipoproteins that have led them to be overrepresented among amyloidogenic proteins. Additionally, we aim to distinguish mutations leading to amyloidosis from those that lead to inherited dyslipidemias. RECENT FINDINGS: Apolipoproteins are becoming increasingly recognized in hereditary forms of amyloidosis. Although mutations in APOA1 and APOA2 have been well established in hereditary amyloidosis, new mutations are still being detected, providing further insight into the pathogenesis of apolipoprotein-related amyloidosis. Furthermore, amyloidogenic mutations in APOC2 and APOC3 have more recently been described. Although no hereditary mutations in APOE or APOA4 have been described to date, both protein products are amyloidogenic and frequently found within amyloid deposits. SUMMARY: Understanding the underlying apolipoprotein mutations that contribute to hereditary amyloidosis may help improve understanding of this rare but serious disorder and could open the door for targeted therapies and the potential development of new treatment options.
