NIH grant: Elucidating the role of LACTB2 in liver metabolic development (1R01DK144257-01A1)

retained text

NIH grant 1R01DK144257-01A1: Elucidating the role of LACTB2 in liver metabolic development
Institute: {'code': 'DK', 'abbreviation': 'NIDDK', 'name': 'National Institute of Diabetes and Digestive and Kidney Diseases', 'admin_org_id': '12500020', 'admin_funding_url': ''}. PI: Min  Ni. Award: $682894.
Start: 2026-08-15T00:00:00.
PROJECT SUMMARY
The liver at birth is immature and requires significant growth and differentiation to develop into the body’s primary
metabolic organ. Despite advances in uncovering transcriptional regulators and signaling pathways involved in
liver development, the underlying metabolic programs that support its maturation remain largely unexplored. To
address this knowledge gap, our research focuses on identifying critical metabolic regulators and pathways
required for liver maturation, recognizing that nutrient metabolism is fundamental for the liver’s growth and
primary function during postnatal development. To gain a time-resolved view of liver metabolic maturation, we
performed ‘first-in-kind’ metabolomic profiling in both male and female mouse livers across six postnatal stages,
from neonate to adulthood. This temporal analysis identified two key metabolic transition phases: one associated
with rapid liver growth and the other with post-weaning dietary adaptation, suggesting that specific metabolic
pathways regulate liver maturation during these periods. Notably, our previous studies identified a loss-of-
function mutation in LACTB2, a newly discovered mitochondrial RNA endoribonuclease, in an infant boy with
severe liver dysfunction. LACTB2 was significantly upregulated during both critical transition phases of liver
metabolic maturation. Mice deficient in LACTB2 exhibited impaired liver development, metabolic dysfunction,
and post-weaning mortality, underscoring the essential role of LACTB2 as a metabolic regulator in liver
development. Building on these findings, the objective of this project is to determine how nutritional changes
impact normal liver development and elucidate how LACTB2 regulates key metabolic processes to support liver
maturation. We hypothesize that LACTB2 controls mitochondrial RNA homeostasis to reinforce mitochondrial
DNA-encoded OXPHOS protein expression during critical metabolic transition phases. To test this hypothesis,
we will define the functional impact of nutrient shifts on normal liver development in both sexes (Aim 1), assess
how LACTB2 deficiency affects liver metabolic maturation (Aim 2), and determine the molecular mechanisms by
which LACTB2 regulates mitochondrial function in hepatocytes (Aim 3). These studies will uncover novel
mechanisms by which the liver orchestrates metabolic processes to support its maturation, offering new insights
into strategies for modulating metabolism to enhance liver function and development.

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