Amino Acids as a Major Carbon Source for Hepatic Lipogenesis

Through a series of epidemiological analyses, flux analyses, and genetic interventions, we identified amino acid as a primary carbon source in hepatic de novo lipogenesis (DNL), and revealed the vital role of dietary protein in non-alcoholic fatty liver disease (NAFLD). To evaluate whether this finding can be applied to treat hepatic steatosis, we implemented protein restriction in obese mice. A short-term low-protein diet (5% kcal protein intake) not only reduced food intake and body weight gain of mice but also ameliorated hepatic lipid accumulation and liver damage. Here, we conducted RNA sequencing for liver samples from these mice and demonstrated a global downregulation of lipogenic genes. Together, this study uncovers a significant role of amino acids in hepatic DNL, and suggests a previously unappreciated target for NAFLD. To investigate the effect of protein restriction on liver metabolism and hepatic steatosis, we fed 8-week-old genetic obese (ob/ob) male mice with either standard protein diet (SPD, 25% kcal protein) or low protein diet (LPD, 5% kcal protein) for 3 weeks. The liver samples were then harvested and snap-frozen in liquid nitrogen for subsequent transcriptomic analysis.