Global TMEM68 deletion alters hepatic lipid storage and energy metabolism in mice
A global knockout of the triglyceride‑synthesizing membrane protein TMEM68 in mice produces a temporary drop in liver triglyceride stores and circulating ketone bodies, accompanied by broad changes in hepatic lipid classes and gene expression linked to fatty‑acid metabolism and ketogenesis.
Study and findings
The authors generated a germline Tmem68 knockout mouse and examined hepatic lipid and energy parameters around the fourth post‑natal week. Compared with wild‑type littermates, knockout mice displayed a transient decrease in hepatic triglyceride content and lower plasma ketone concentrations. Lipidomic profiling of liver tissue revealed reduced levels of specific acylglycerols and fatty acids, a shift in glycerophospholipid composition, and an accumulation of polar ether lipids. Primary hepatocytes isolated from knockout animals showed fewer lipid droplets and lower intracellular triglyceride stores. Transcriptomic analysis indicated down‑regulation of genes governing fatty‑acid oxidation, ketogenesis, and related pathways. Additionally, hepatic cholesterol ester pools were diminished and bile‑acid species were altered.
Clinical interpretation
These data identify TMEM68 as a positive regulator of hepatic triglyceride accumulation and suggest that its activity influences broader aspects of liver energy balance, including ketone‑body production and bile‑acid metabolism. While the study is confined to mice, the findings raise the possibility that TMEM68 could modulate lipid storage and metabolic flexibility in human liver, a concept relevant to disorders of dyslipidemia and non‑alcoholic fatty liver disease. However, the transient nature of the observed triglyceride reduction and the lack of functional outcomes (e.g., glucose tolerance, insulin sensitivity) limit direct extrapolation to clinical contexts.
Limitations and open questions
The investigation relied on a global knockout, so tissue‑specific contributions of TMEM68 cannot be isolated. The phenotype was assessed at a single developmental window; longer‑term effects on hepatic lipid homeostasis remain unknown. Moreover, the study did not evaluate systemic metabolic consequences such as body weight, energy expenditure, or response to dietary challenges. Future work using liver‑restricted deletion and longitudinal metabolic phenotyping would clarify whether TMEM68 is a viable target for modulating hepatic lipid storage in disease.
Source
Wang H et al. Global deletion of the triglyceride‑synthesizing enzyme TMEM68 disrupts hepatic lipid homeostasis in mice. J Physiol Biochem. 2026; PMID 42853368.