Investigation of parenteral nutrition-induced hepatotoxicity using human liver spheroid co-cultures

Abstract

Parenteral nutrition (PN) is typically administered to individuals with gastrointestinal dysfunction, a contraindication for enteral feeding, and a need for nutritional therapy. When PN is the only energy source in patients, it is defined as total parenteral nutrition (TPN). TPN is a life-saving approach for different patient populations, both in infants and adults. However, despite numerous benefits, TPN can cause adverse effects, including metabolic disorders and liver injury. TPN-associated liver injury, known as intestinal failure-associated liver disease (IFALD), represents a significant problem affecting up to 90% of individuals receiving TPN. IFALD pathogenesis is complex, depending on the TPN components as well as on the patient’s medical conditions. Despite numerous animal studies and clinical observations, the molecular mechanisms driving IFALD remain largely unknown. The present study was set up to elucidate the mechanisms underlying IFALD. For this purpose, human liver spheroid co-cultures were treated with a TPN mixture, followed by RNA sequencing analysis. Subsequently, following exposure to TPN and its single nutritional components, several key events of liver injury, including mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, apoptosis, and lipid accumulation (steatosis), were studied using various techniques. It was found that prolonged exposure to TPN substantially changes the transcriptome profile of liver spheroids and affects multiple metabolic and signaling pathways contributing to liver injury. Moreover, TPN and its main components, especially lipid emulsion, induce changes in all key events measured and trigger steatosis.

Dataset on transcriptomic profiling of parenteral nutrition-induced hepatotoxicity in a human liver in vitro model

“…The use of a human-centered in vitro system (liver spheroids co-cultures consisting of hepatocytes and hepatic stellate cells) in combination with high-throughput RNA sequencing and generation of the transcriptomic profile of exposure to TPN can allow for in-depth investigation of TPN-associated liver injury at the mechanistic level. In addition to the primary research article studying the hepatotoxic potential of TPN [ 3 ], the hereby presented data can serve to support and complement further mechanistic studies on intestinal failure-associated liver disease pathogenesis and progression.…”

“…During 3 independent experiments, the spheroid co-cultures were exposed to 1 % TPN for either 24 h or 144 h, in order to assess the hepatotoxic potential of TPN [ 4 , 5 ]. The concentration of 1 % TPN was selected based on the cell viability results, as shown in the related research article [ 3 ]. The control condition consisted of liver spheroid co-cultures incubated with the cell culture medium solely for 24 h or 144 h. After the incubation of 24 and 144 h, liver spheroid co-cultures exposed to 1 % TPN and respective controls were sampled and RNA was isolated.…”