Impaired Hepatic Phosphatidylcholine Synthesis Leads to Cholestasis in Mice Challenged With a High‐Fat Diet

Abstract

Phosphatidylethanolamine N‐methyltransferase (PEMT) is a hepatic integral membrane protein localized to the endoplasmic reticulum (ER). PEMT catalyzes approximately 30% of hepatic phosphatidylcholine (PC) biosynthesis. Pemt–/– mice fed a high‐fat diet (HFD) develop steatohepatitis. Interestingly, portions of the ER located close to the canaliculus are enriched in PEMT. Phospholipid balance and asymmetrical distribution by adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) on the canalicular membrane is required for membrane integrity and biliary processes. We hypothesized that PEMT is an important supplier of PC to the canaliculus and that PEMT activity is critical for the maintenance of canalicular membrane integrity and bile formation following HFD feeding when there is an increase in overall hepatic PC demand. Pemt+/+ and Pemt–/– mice were fed a chow diet, an HFD, or a choline‐supplemented HFD. Plasma and hepatic indices of liver function and parameters of bile formation were determined. Pemt–/– mice developed cholestasis, i.e, elevated plasma bile acid (BA) concentrations and decreased biliary secretion rates of BAs and PC, during HFD feeding. The maximal BA secretory rate was reduced more than 70% in HFD‐fed Pemt–/– mice. Hepatic ABCB11/bile salt export protein, responsible for BA secretion, was decreased in Pemt–/– mice and appeared to be retained intracellularly. Canalicular membranes of HFD‐fed Pemt–/– mice contained fewer invaginations and displayed a smaller surface area than Pemt+/+ mice. Choline supplementation (CS) prevented and reversed the development of HFD‐induced cholestasis. Conclusion: We propose that hepatic PC availability is critical for bile formation. Dietary CS might be a potential noninvasive therapy for a specific subset of patients with cholestasis.

Lipidomic and Proteomic Alterations Induced by Even and Odd Medium-Chain Fatty Acids on Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

“…In fibroblasts from VLCADD patients we observed a significant reduction of PC upon C8 and of PE after incubation with both mc-FAs (Figure 1C). In parallel with these findings, after incubation with C7 we observed an increment in the molar ratio of PC/PE (4.83 vs. 3.85) (Table 1) compared to untreated cell lines, which may be indicative of an adaptive mechanism to reduce endoplasmic reticulum stress in response to increased available substrates for energy production [24]. In addition, the concentration of storage lipids DAG and triacylglycerides (TAG) as well as of SM and hexosylceramides (HEX) increased significantly after incubation of both mc-FAs (Figure 1D), whereas the total cardiolipin (CL) content did not change significantly.…”

Effects of dietary choline on liver lipid composition, liver histology and plasma biochemistry of juvenile yellowtail kingfish (Seriola lalandi)

“…Furthermore, Wan et al (88) established that impaired liver PC synthesis (Pemt -/-) in mice fed high-fat diet led to a decrease in biliary secretion of bile acid and PC, decreased It is unclear whether hepatocyte necrosis and enlarged nuclei was induced directly or indirectly from choline-deficiency; however, the results clearly showed a significant reduction in necrotic hepatocytes when juvenile YTK was fed higher than sufficient dose of choline (Diet 5; 6.22 g/kg diet). MMCs are aggregates of melanomacrophages (pigmented phagocytes) generally found in lymphoid tissues (89) .…”

“…For example, mdr2 gene (regulates biliary phospholipid secretion) knockout mice showed bile duct inflammation and proliferation (86) ; oxidative stress and apoptosis in fetal rats have also been linked to elevated bile acids (87) . Furthermore, Wan et al (88) established that impaired liver PC synthesis (Pemt -/-) in mice fed high-fat diet led to a decrease in biliary secretion of bile acid and PC, decreased liver PC:PE ratio and an increase in plasma bile acids (cholestasis). Unfortunately, to the best of our knowledge, such effects on liver have not been reported in choline-related studies in teleost fish.…”

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

“…Studies in mice indicate that in addition to steatosis, reduced PC availability may also contribute to hepatic injury in NASH. For example, high-fat diet (HFD)-fed PEMT-deficient mice develop more severe hepatic inflammation and fibrosis, likely due to cholestasis [ 73 ]. Similarly, patients with histological NASH and methionine- and choline-deficient-fed mice [ 74 ] displayed increased hepatic glutaminase 1 (GLS1), which is associated with reduced PC synthesis.…”