Cover Story Current Issue
Maternal nutrition exerts profound and lasting effects on infant development, with implications extending beyond somatic growth to long-term brain function and metabolic health. For example, newborns from mothers with obesity or diabetes exhibit increased susceptibility to metabolic disorders, including insulin resistance (IR) and type 2 diabetes (T2D), often emerging in childhood or adolescence. While genetic inheritance contributes to this intergenerational risk, early-life nutritional exposures are increasingly recognized as primary drivers of persistent metabolic programming. Among key classes of nutrients, branched-chain amino acids (BCAAs)—leucine, isoleucine, and valine—have emerged as potent modulators of metabolic health in human adults. Elevated circulating BCAAs are among the most accurate predictors of future insulin resistance (IR) and T2D, with a two-fold increase in serum levels conferring a 2.5-fold risk of diabetes onset within 6–10 years. This elevation can directly cause organ toxicity, exacerbating metabolic deficits in a feed-forward loop. However, the extent to which maternal BCAA overnutrition during gestation and lactation impacts offspring metabolic programming and predisposes to dysfunction remains unclear.
Current Issue
Effect of free fatty acids on TGF-β1 mediated fibrogenesis in hepatic stellate cells
Effect of free fatty acids on TGF-β1 mediated fibrogenesis in hepatic stellate cells
Abstract/objective
Metabolic associated steatotic liver disease (MASLD) is the most prevalent liver disorder and a major risk factor for hepatic fibrosis. Activated hepatic stellate cells (HSCs) are the primary source of collagen production in the liver, contributing to fibrosis. However, the mechanisms by which HSCs reprogram their metabolism to support sustained collagen production, particularly in a lipid-rich environment such as MASLD, remain inadequately understood. In this study, we investigated the effect of extracellular fatty acids on HSC substrate metabolism, HSC activation, and collagen synthesis.
Methods
Immortalized human HSCs (LX-2 cells) were cultured with or without transforming growth factor-beta 1 (TGF-β1) and varying concentrations of palmitate or oleate. Cellular lipid composition was assessed by mass spectrometry lipidomics. Fatty acid metabolism was assessed using radiometric techniques and isotopic labelling experiments using 13C-glucose or 13C-palmitate. HSC activation was assessed by measuring ACTA2, TGFB1, and COL1A1 mRNA levels and collagen secretion by ELISA.
Results
TGF-β1 reduced the abundance of many lipid types in LX-2 cells. Exogenous palmitate did not increase HSC activation, as determined by ACTA2, TGFB1, COL1A1 mRNA levels. Palmitate potentiated TGF-β1 induced collagen secretion but not in the presence of oleate. Palmitate reduced glucose incorporation into glycine in activated HSCs and induced a reciprocal increase in palmitate incorporation into glycine, most likely via carbons derived from TCA cycle intermediates. Pharmacological inhibition of fatty acid uptake reduced TGF-β1-mediated collagen secretion.
Conclusions
These results suggest that in activated HSCs, palmitate oxidation is reduced and that TCA cycle intermediates derived from palmitate are used as carbon sources for amino acid production that supports collagen synthesis and secretion.
Articles in Press
Effect of free fatty acids on TGF-β1 mediated fibrogenesis in hepatic stellate cells
Effect of free fatty acids on TGF-β1 mediated fibrogenesis in hepatic stellate cells
Abstract/objective
Metabolic associated steatotic liver disease (MASLD) is the most prevalent liver disorder and a major risk factor for hepatic fibrosis. Activated hepatic stellate cells (HSCs) are the primary source of collagen production in the liver, contributing to fibrosis. However, the mechanisms by which HSCs reprogram their metabolism to support sustained collagen production, particularly in a lipid-rich environment such as MASLD, remain inadequately understood. In this study, we investigated the effect of extracellular fatty acids on HSC substrate metabolism, HSC activation, and collagen synthesis.
Methods
Immortalized human HSCs (LX-2 cells) were cultured with or without transforming growth factor-beta 1 (TGF-β1) and varying concentrations of palmitate or oleate. Cellular lipid composition was assessed by mass spectrometry lipidomics. Fatty acid metabolism was assessed using radiometric techniques and isotopic labelling experiments using 13C-glucose or 13C-palmitate. HSC activation was assessed by measuring ACTA2, TGFB1, and COL1A1 mRNA levels and collagen secretion by ELISA.
Results
TGF-β1 reduced the abundance of many lipid types in LX-2 cells. Exogenous palmitate did not increase HSC activation, as determined by ACTA2, TGFB1, COL1A1 mRNA levels. Palmitate potentiated TGF-β1 induced collagen secretion but not in the presence of oleate. Palmitate reduced glucose incorporation into glycine in activated HSCs and induced a reciprocal increase in palmitate incorporation into glycine, most likely via carbons derived from TCA cycle intermediates. Pharmacological inhibition of fatty acid uptake reduced TGF-β1-mediated collagen secretion.
Conclusions
These results suggest that in activated HSCs, palmitate oxidation is reduced and that TCA cycle intermediates derived from palmitate are used as carbon sources for amino acid production that supports collagen synthesis and secretion.
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13th
Helmholtz Diabetes Conference
Munich, 21-23. Sep 2026
2024 impact factor: 6.6
You are what you eat
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