Gene Therapy for Progressive Familial Intrahepatic Cholestasis: Current Progress and Future Prospects.

Progressive Familial Intrahepatic Cholestasis (PFIC) are inherited severe liver disorders presenting early in life, with high serum bile salt and bilirubin levels. Six types have been reported, two of these are caused by deficiency of an ABC transporter; ABCB11 (bile salt export pump) in type 2; ABCB4 (phosphatidylcholine floppase) in type 3. In addition, ABCB11 function is affected in 3 other types of PFIC. A lack of effective treatment makes a liver transplantation necessary in most patients. In view of long-term adverse effects, for instance due to life-long immune suppression needed to prevent organ rejection, gene therapy could be a preferable approach, as supported by proof of concept in animal models for PFIC3. This review discusses the feasibility of gene therapy as an alternative for liver transplantation for all forms of PFIC based on their pathological mechanism. Conclusion: Using presently available gene therapy vectors, major hurdles need to be overcome to make gene therapy for all types of PFIC a reality.

NTCP deficiency in mice protects against obesity and hepatosteatosis.

Bile acids play a major role in the regulation of lipid and energy metabolism. Here we propose the hepatic bile acid uptake transporter Na+ taurocholate co-transporting polypeptide (NTCP) as a target to prolong postprandial bile acid elevations in plasma. Reducing hepatic clearance of bile acids from plasma by genetic deletion of NTCP moderately increased plasma bile acid levels, reduced diet-induced obesity, attenuated hepatic steatosis, and lowered plasma cholesterol levels. NTCP-G protein-coupled bile acid receptor (TGR5) double knockout mice were equally protected against diet-induced-obesity as NTCP single knockout mice. NTCP knockout mice displayed decreased intestinal fat absorption and a trend towards higher fecal energy output. Furthermore, NTCP deficiency was associated with an increased uncoupled respiration in brown adipose tissue, leading to increased energy expenditure. We conclude that targeting NTCP-mediated bile acid uptake can be a novel approach to treat obesity and obesity-related hepatosteatosis by simultaneously dampening intestinal fat absorption and increasing energy expenditure.

A systematic approach to the management of cholestatic pruritus in primary biliary cirrhosis.

Pruritus (itch) is an important symptom of primary biliary cirrhosis (PBC), an archetypal cholestatic liver disease. Cholestatic pruritus can be a debilitating symptom causing significant deterioration in patients' quality of life. Effective management of pruritus in PBC involves awareness among clinicians to adequately assess its severity, and treatment with specific drug therapies in line with current practice guidelines. In PBC, antipruritic drugs are not universally effective and/or have significant side effects, and despite best efforts with various combinations of drugs, some patients remain significantly symptomatic, eventually opting for invasive or experimental treatments. Therefore, there is a clear unmet need for better alternative treatments for patients with refractory or intractable cholestatic pruritus. Recent advances in the understanding of pathogenesis of cholestatic pruritus and bile acid physiology have raised hopes for novel therapies, some of which are currently under trial. In this review, we aim to provide a practical guide to the management of this important and complex problem, discussing current knowledge and recent advances in the pathogenesis, summarise the evidence base for available therapeutic approaches and update potential novel future therapies for the management of pruritus in PBC.

Targeting the ABCB4 gene to control cholesterol homeostasis.

INTRODUCTION: Multidrug resistance 3 (MDR3) P-glycoprotein is a lipid floppase that is encoded by the ATP-binding cassette sub-family B member 4 (ABCB4) gene and plays a crucial role in proper bile formation by transporting phosphatidylcholine across the canalicular plasma membrane of the hepatocyte into bile. The relevance of this function is underscored by the severe pathology that develops in patients with ABCB4 deficiency. This deficiency leads to the destruction of hepatocytes and cholangiocytes by bile salts, because their cytolytic action is not reduced by formation of mixed micelles with phospholipid. AREAS COVERED: Evidence that phospholipid secretion into bile is also essential for biliary cholesterol secretion as cholesterol dissolves much better in mixed micelles of bile salts and phospholipid than in pure bile salt micelles. As a consequence, net biliary cholesterol secretion depends on the amount of phospholipid secreted and hence, the expression of ABCB4 indirectly determines biliary cholesterol output. EXPERT OPINION: It can be argued that upregulation of the ABCB4 gene expression may not only be beneficial for liver pathology in patients with partial ABCB4 deficiency, but also for the prevention of gallstone formation and optimal cholesterol disposition in a much larger population.